Apparatus and method for indicating treatment site locations for phototherapy to the brain

ABSTRACT

An apparatus and method for indicating treatment site locations for phototherapy to the brain are disclosed. In some embodiments, the apparatus is a headpiece wearable by a patient. The headpiece includes a body adapted to be worn over at least a portion of the patient&#39;s scalp and a plurality of position indicators corresponding to a plurality of treatment site locations at the patient&#39;s scalp where a light source is to be sequentially positioned such that light from the light source is sequentially applied to irradiate at least a portion of the patient&#39;s brain. At least one of the position indicators includes an optically transmissive portion having an area of at least 1 cm2 through which the light propagates.

CLAIM OF PRIORITY

This application is a continuation-in-part application of U.S. patentapplication Ser. No. 11/385,980, filed Mar. 21, 2006, which claims thebenefit of U.S. Provisional Application No. 60/763,261, filed Jan. 30,2006. This application is also a continuation-in-part application ofU.S. patent application Ser. No. 12/403,824, filed Mar. 13, 2009, whichis a continuation-in-part application of U.S. patent application Ser.No. 12/389,294, filed Feb. 19, 2009, and which claims the benefit ofpriority to U.S. Provisional Application No. 61/037,668, filed Mar. 18,2008. The entire content of each of these applications is herebyexpressly incorporated herein by reference.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates in general to phototherapy, and moreparticularly, to novel apparatuses and methods for phototherapy of braintissue.

Description of the Related Art

There are numerous neurologic conditions, such as neurodegenerativediseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophiclateral sclerosis), Huntington's disease, demyelinating diseases (e.g.,multiple sclerosis), cranial nerve palsies, traumatic brain injury,stroke, depression, and spinal cord injury which could possibly benefitfrom application of phototherapy. Most of these conditions causesignificant morbidity and mortality and involve tremendous burden tosociety, families and caregivers. Many neurologic conditions have nocurrently available effective therapies or the therapies that areavailable are not adequate to restore functional recovery, sustainquality of life, or halt disease progression.

One example of a neurologic condition that remains a major unmet medicalneed is stroke, also called cerebrovascular accident (CVA). Stroke iscaused by a sudden disruption of blood flow to a discrete area of thebrain that is brought on by the lodging of a clot in an artery supplyingblood to an area of the brain (called an ischemic stroke), or by acerebral hemorrhage due to a ruptured aneurysm or a burst artery (calleda hemorrhagic stroke). There are over 750.000 stroke victims per year inthe United States, and approximately 85% of all strokes are ischemic and15% are hemorrhagic. The consequence of stroke is a loss of function inthe affected brain region and concomitant loss of bodily function inareas of the body controlled by the affected brain region. Dependingupon the extent and location of the primary insult in the brain, loss offunction varies greatly from mild or severe, and may be temporary orpermanent. Lifestyle factors such as smoking, diet, level of physicalactivity and high cholesterol increase the risk of stroke, and thusstroke is a major cause of human suffering in developed nations. Strokeis the third leading cause of death in most developed nations, includingthe United States.

Stroke treatment is often restricted to providing basic life support atthe time of the stroke, followed by rehabilitation. Currently, the onlyFDA-cleared treatment of ischemic stroke involves thrombolytic therapyusing tissue plasminogen activator (tPA). However, tPA can only be usedwithin three hours of stroke onset and has several contraindications,therefore, only a small percentage of stroke victims receive this drug.

Traumatic brain injury (TBI) occurs when a sudden physical trauma (e.g.,crush or compression injury in the central nervous system, including acrush or compression injury of the brain, spinal cord, nerves or retina,or any acute injury or insult producing cell death) causes damage to thehead. For example, a sudden and/or violent blow to the head or an objectpiercing the skull and entering brain tissue can result in TBI. Theextent of damage to the brain can be severe, however even mild andmoderate TBI has been associated with neurological sequelae that can belong lasting. Development of neurodegenerative conditions has beenassociated with TBI. TBI can result in a sudden disruption of blood flowto a discrete area of the brain. The consequence of stroke or TBI can bea loss of function in the affected brain region and concomitant loss ofbodily function in areas of the body controlled by the affected brainregion. Depending upon the extent and location of the primary insult inthe brain, loss of function varies greatly from mild or severe, and maybe temporary or permanent.

A high level of interest and clinical need remains in finding new andimproved therapeutic interventions for treatment of stroke and otherneurologic conditions that continue to devastate millions of lives eachyear and where few effective therapies exist.

SUMMARY OF THE INVENTION

In certain embodiments, an apparatus is wearable by a patient fortreating the patient's brain. The apparatus comprises a body adapted tobe worn over at least a portion of the patient's scalp. The apparatusfurther comprises a plurality of indicators corresponding to a pluralityof treatment site locations at the patient's scalp where a light sourceis to be sequentially positioned such that light from the light sourceis sequentially applied to irradiate at least a portion of the patient'sbrain. At least one of the indicators comprises an opticallytransmissive portion of the body having an area of at least 1 cm²through which the light propagates.

In certain embodiments, an apparatus is wearable by a patient fortreating the patient's brain. The apparatus comprises means foridentifying a plurality of treatment site locations at the patient'sscalp where light is to be applied to irradiate at least a portion ofthe patient's brain. The apparatus further comprises means forindicating to an operator a sequential order for irradiating thetreatment site locations.

In certain embodiments, a method of treating a patient's brain comprisesnoninvasively irradiating a first area of at least 1 cm² of thepatient's scalp with laser light during a first time period. The methodfurther comprises noninvasively irradiating a second area of at least 1cm² of the patient's scalp with laser light during a second time period,wherein the first area and the second area do not overlap one another.The first time period and the second time period do not overlap oneanother.

In certain embodiments, a method for denoting a brain phototherapyprocedure comprises identifying a plurality of treatment site locationsat a patient's scalp. The method further comprises indicating asequential order for irradiation of the treatment site locations. Atleast one of the treatment site locations has an area of at least 1 cm².

In certain embodiments, a headpiece is wearable by a patient fortreating the patient's brain. The headpiece comprises a plurality ofposition indicators configured to indicate corresponding treatment sitelocations at which light is to be applied to non-invasively irradiate atleast a portion of the patient's brain. At least one position indicatorof the plurality of position indicators comprises an opticallytransmissive region and a mating portion configured to releasably matewith a complementary portion of a light source. The headpiece isconfigured to conform to at least a portion of the patient's scalp.

In certain embodiments, a headpiece is wearable by a patient fortreating the patient's brain. The headpiece comprises a body configuredto generally conform to at least a portion of the patient's scalp. Theheadpiece further comprises a plurality of position indicatorsconfigured to indicate corresponding treatment site locations of thepatient's scalp at which light is to be applied to non-invasivelyirradiate at least a portion of the patient's brain. At least oneposition indicator of the plurality of position indicators comprising anaperture and a mating portion configured to releasably mate with acomplementary portion of a light source. The headpiece also comprises aplurality of labels configured to indicate a predetermined treatmentsequence for sequentially applying light from the light source to thetreatment site locations. The headpiece further comprises a retainingmember extending between a first side of the headpiece and a second sideof the headpiece. The retaining member is configured to secure theheadpiece to the head of the patient.

In certain embodiments, a system for providing phototherapy to at leasta portion of a patient's brain comprises a light emitting device and awearable headpiece. The light source comprises a light source configuredto generate light comprising one or more wavelengths in a range of about630 nm to about 1064 nanometers, an output optical element in opticalcommunication with the light source, and a docking element. The outputoptical element is configured to emit at least a portion of the lightgenerated by the light source. The wearable headpiece comprises aplurality of position indicators configured to indicate correspondingtreatment site locations of the patient's scalp at which the light is tobe applied to irradiate at least a portion of the patient's brain. Atleast one position indicator of the plurality of position indicatorscomprises an optically transmissive region and a mating portionconfigured to releasably mate with the docking element of the lightemitting device.

In certain embodiments, a method of providing phototherapy to at least aportion of a patient's brain comprises positioning a wearable headpieceon the patient's head. The method further comprises reversiblymechanically coupling a light source to a first portion of the headpiecewhile the headpiece is on the patient's head, wherein the headpieceapplies a first force to the light source such that light emitted by thelight source non-invasively irradiates at least a first portion of thepatient's brain by propagating through a first treatment site locationof the patient's scalp. The method also comprises removing the lightsource from the first portion of the headpiece while the headpieceremains on the patient's head.

For purposes of summarizing the present invention, certain aspects,advantages, and novel features of the present invention have beendescribed herein above. It is to be understood, however, that notnecessarily all such advantages may be achieved in accordance with anyparticular embodiment of the present invention. Thus, the presentinvention may be embodied or carried out in a manner that achieves oroptimizes one advantage or group of advantages as taught herein withoutnecessarily achieving other advantages as may be taught or suggestedherein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates an example beam delivery apparatus inaccordance with certain embodiments described herein.

FIG. 2A schematically illustrates a cross-sectional view of an exampleoutput optical assembly in accordance with certain embodiments describedherein.

FIG. 2B schematically illustrates another example output opticalassembly in accordance with certain embodiments described herein.

FIGS. 3A and 3B schematically illustrate the diffusive effect on thelight by the output optical assembly.

FIGS. 4A and 4B schematically illustrate cross-sectional views of twoexample beam delivery apparatuses in accordance with certain embodimentsdescribed herein.

FIG. 5 schematically illustrates an example fiber alignment mechanism inaccordance with certain embodiments described herein.

FIG. 6 schematically illustrates an example mirror compatible withcertain embodiments described herein.

FIG. 7 schematically illustrates an example first optical path of lightemitted from the optical fiber in accordance with certain embodimentsdescribed herein.

FIG. 8 schematically illustrates an example second optical path ofradiation received by the sensor.

FIG. 9A schematically illustrates an example thermoelectric element andFIG. 9B schematically illustrates two views of an example thermalconduit in accordance with certain embodiments described herein.

FIG. 10A schematically illustrates another example thermoelectricelement and FIG. 10B schematically illustrates two views of anotherexample thermal conduit in accordance with certain embodiments describedherein.

FIG. 11A schematically illustrates a cross-sectional view of an exampleheat sink and FIG. 11B schematically illustrates another example heatsink in accordance with certain embodiments described herein.

FIGS. 12A and 12B schematically illustrate two example configurations ofthe window with the thermoelectric assembly.

FIG. 13A schematically illustrates an example chassis for supporting thevarious components of the beam delivery apparatus within the housing inaccordance with certain embodiments described herein.

FIG. 13B schematically illustrates another example chassis in accordancewith certain embodiments described herein.

FIG. 14A schematically illustrates a cross-sectional view of an exampleconfiguration of the chassis and the housing in accordance with certainembodiments described herein.

FIGS. 14B and 14C schematically illustrate another example configurationof the chassis and the housing in accordance with certain embodimentsdescribed herein.

FIGS. 15A and 15B schematically illustrate two states of an examplesensor in accordance with certain embodiments described herein.

FIGS. 15C and 15D schematically illustrate two states of another examplesensor in accordance with certain embodiments described herein.

FIGS. 16A and 16B schematically illustrate two example configurations ofthe trigger force spring and trigger force adjustment mechanism inaccordance with certain embodiments described herein.

FIG. 17 schematically illustrates an example lens assembly sensor inaccordance with certain embodiments described herein.

FIG. 18 is a block diagram of a control circuit comprising aprogrammable controller for controlling a light source according toembodiments described herein.

FIG. 19A is a graph of the transmittance of light through blood (inarbitrary units) as a function of wavelength.

FIG. 19B is a graph of the absorption of light by brain tissue.

FIG. 19C shows the efficiency of energy delivery as a function ofwavelength.

FIG. 20 shows measured absorption of 808 nanometer light through variousrat tissues.

FIGS. 21A-21D schematically illustrate example pulses in accordance withcertain embodiments described herein.

FIGS. 22A-22C schematically illustrate an embodiment in which theapparatus is placed in thermal communication sequentially with aplurality of treatment sites corresponding to portions of the patient'sscalp.

FIG. 23A schematically illustrates an example apparatus which iswearable by a patient for treating the patient's brain.

FIGS. 23B and 23C schematically illustrate the left-side and right-sideof an example apparatus, respectively, with labels substantiallycovering the indicators corresponding to the treatment sites.

FIG. 23D schematically illustrates an example labeling configurationfrom above a flattened view of the apparatus of FIGS. 23B and 23C.

FIGS. 23E-23H illustrate an example embodiment of a wearable apparatusfor use in treating the patient's brain with phototherapy.

FIGS. 23I-23M illustrate alternative example embodiments of a wearableapparatus for use in treating the patient's brain with phototherapy.

FIG. 24 schematically illustrates an example embodiment of a wearableheadpiece that may be configured to position a light delivery apparatus.

FIGS. 25-28 are flow diagrams of example methods for irradiating asurface with light.

FIG. 29A is a flow diagram of an example method for controllablyexposing at least one predetermined area of a patient's scalp to laserlight to irradiate the patient's brain.

FIG. 29B is a flow diagram of an example method for providingphototherapy to at least a portion of a patient's brain using a wearableheadpiece.

FIG. 30 is a flow diagram of another example method for treating apatient's brain.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Low level light therapy (“LLLT”) or phototherapy involves therapeuticadministration of light energy to a patient at lower irradiances thanthose used for cutting, cauterizing, or ablating biological tissue,resulting in desirable biostimulatory effects while leaving tissueundamaged. In non-invasive phototherapy, it is desirable to apply anefficacious amount of light energy to the internal tissue to be treatedusing light sources positioned outside the body. (See, e.g., U.S. Pat.Nos. 6,537,304 and 6,918,922, both of which are incorporated in theirentireties by reference herein.)

Laser therapy has been shown to be effective in a variety of settings,including treating lymphoedema and muscular trauma, and carpal tunnelsyndrome. Recent studies have shown that laser-generated infraredradiation is able to penetrate various tissues, including the brain, andto modify function. In addition, laser-generated infrared radiation caninduce effects including, but not limited to, angiogenesis, modifygrowth factor (transforming growth factor-β) signaling pathways, andenhance protein synthesis.

However, absorption of the light energy by intervening tissue can limitthe amount of light energy delivered to the target tissue site, whileheating the intervening tissue. In addition, scattering of the lightenergy by intervening tissue can limit the irradiance (or power density)or energy density delivered to the target tissue site. Brute forceattempts to circumvent these effects by increasing the power and/orirradiance applied to the outside surface of the body can result indamage (e.g., burning) of the intervening tissue. For example, a patientexperiencing TBI can have a significant amount of bleeding within theskull (e.g., “blood in the field”), and this blood can absorb theapplied light, thereby inhibiting propagation of light energy to braintissue below the blood-filled region and heating up.

Non-invasive phototherapy methods are circumscribed by setting selectedtreatment parameters within specified limits so as to preferably avoiddamaging the intervening tissue. A review of the existing scientificliterature in this field would cast doubt on whether a set ofundamaging, yet efficacious, parameters could be found for treatingneurologic conditions. However, certain embodiments, as describedherein, provide devices and methods which can achieve this goal.

Such embodiments may include selecting a wavelength of light at whichthe absorption by intervening tissue is below a damaging level. Suchembodiments may also include setting the power output of the lightsource at low, yet efficacious, irradiances (e.g., between approximately100 μW/cm² to approximately 10 W/cm²) at the target tissue site, settingthe temporal profile of the light applied to the head (e.g., temporalpulse widths, temporal pulse shapes, duty cycles, pulse frequencies),and time periods of application of the light energy at hundreds ofmicroseconds to minutes to achieve an efficacious energy density at thetarget tissue site being treated. Other parameters can also be varied inthe use of phototherapy. These other parameters contribute to the lightenergy that is actually delivered to the treated tissue and may play keyroles in the efficacy of phototherapy. In certain embodiments, theirradiated portion of the brain can comprise the entire brain.

In certain embodiments, the target area of the patient's brain includesthe area of injury, e.g., to neurons within the “zone of danger.” Inother embodiments, the target area includes portions of the brain notwithin the zone of danger. Information regarding the biomedicalmechanisms or reactions involved in phototherapy is provided by Tiin aI. Karu in “Mechanisms of Low-Power Laser Light Action on CellularLevel”, Proceedings of SPIE Vol. 4159 (2000), Effects of Low-Power Lighton Biological Systems V, Ed. Rachel Lubart, pp. 1-17, and Michael R.Hamblin et al., “Mechanisms of Low Level Light Therapy,” Proc. of SPIE,Vol. 6140, 614001 (2006), each of which is incorporated in its entiretyby reference herein.

In certain embodiments, the apparatuses and methods of phototherapydescribed herein are used to treat physical trauma (e.g., TBI orischemic stroke) or other sources of neurodegeneration. As used herein,the term “neurodegeneration” refers to the process of cell destructionresulting from primary destructive events such as stroke or CVA, as wellas from secondary, delayed and progressive destructive mechanisms thatare invoked by cells due to the occurrence of the primary destructiveevent. Primary destructive events include disease processes or physicalinjury or insult, including stroke, but also include other diseases andconditions such as multiple sclerosis, amylotrophic lateral sclerosis,heat stroke, epilepsy, Alzheimer's disease, dementia resulting fromother causes such as AIDS, cerebral ischemia including focal cerebralischemia, and physical trauma such as crush or compression injury in theCNS, including a crush or compression injury of the brain, spinal cord,nerves or retina, or any acute injury or insult producingneurodegeneration. Secondary destructive mechanisms include anymechanism that leads to the generation and release of neurotoxicmolecules, including but not limited to, apoptosis, depletion ofcellular energy stores because of changes in mitochondrial membranepermeability, release or failure in the reuptake of excessive glutamate,reperfusion injury, and activity of cytokines and inflammation. Bothprimary and secondary mechanisms contribute to forming a “zone ofdanger” for neurons, wherein the neurons in the zone have at leasttemporarily survived the primary destructive event, but are at risk ofdying due to processes having delayed effect.

In certain embodiments, the apparatuses and methods described herein areused to provide neuroprotection. As used herein, the term“neuroprotection” refers to a therapeutic strategy for slowing orpreventing the otherwise irreversible loss of neurons due toneurodegeneration after a primary destructive event, whether theneurodegeneration loss is due to disease mechanisms associated with theprimary destructive event or secondary destructive mechanisms.

In certain embodiments, the apparatuses and methods described herein areused to improve neurologic function, to provide neurologic enhancement,or to regain previously lost neurologic function. The term “neurologicfunction” as used herein includes both cognitive function and motorfunction. The term “neurologic enhancement” as used herein includes bothcognitive enhancement and motor enhancement. The terms “cognitiveenhancement” and “motor enhancement” as used herein refer to theimproving or heightening of cognitive function and motor function,respectively.

The term “cognitive function” as used herein refers to cognition andcognitive or mental processes or functions, including those relating toknowing, thinking, learning, perception, memory (including immediate,recent, or remote memory), and judging. Symptoms of loss of cognitivefunction can also include changes in personality, mood, and behavior ofthe patient. The term “motor function” as used herein refers to thosebodily functions relating to muscular movements, primarily consciousmuscular movements, including motor coordination, performance of simpleand complex motor acts, and the like.

Diseases or conditions affecting neurologic function include, but arenot limited to, Alzheimer's disease, dementia, AIDS or HIV infection,Cruetzfeldt-Jakob disease, head trauma (including single-event traumaand long-term trauma such as multiple concussions or other traumas whichmay result from athletic injury), Lewy body disease, Pick's disease,Parkinson's disease, Huntington's disease, drug or alcohol abuse, braintumors, hydrocephalus, kidney or liver disease, stroke, depression, andother mental diseases which cause disruption in cognitive function, andneurodegeneration.

Beam Delivery Apparatus

The phototherapy methods for the treatment of neurologic conditions(e.g., ischemic stroke, Alzheimer's Disease, Parkinson's Disease,depression, or TBI) described herein may be practiced and describedusing various light delivery systems. Such light delivery systems mayinclude a low level laser therapy apparatus such as that shown anddescribed in U.S. Pat. Nos. 6,214,035; 6,267,780; 6,273,905; 6,290,714;7,303,578; and 7,575,589 and in U.S. Pat. Appl. Publ. Nos. 2005/0107851A1 and 2009/0254154 A1, each of which is incorporated in its entirety byreference herein. For example, in certain embodiments, the lightdelivery apparatus can irradiate a portion of the patient's scalp orskull while cooling the irradiated portion of the scalp or skull. Incertain other embodiments, the irradiated portion of the patient's scalpor skull is not cooled while irradiating the portion of the scalp orskull.

These previously-disclosed light delivery apparatuses were describedprimarily in conjunction with phototherapy treatment of stroke, howeverin certain embodiments, such light delivery apparatuses can also be usedfor phototherapy treatment of other neurologic conditions (e.g.,Alzheimer's Disease, Parkinson's Disease, Huntington's Disease,depression, TBI). A patient who has experienced a TBI may have a portionof their scalp damaged, thereby exposing a portion of their cranium orskull. In certain such embodiments, the light delivery apparatus canirradiate an exposed portion of the cranium or skull without the lightpropagating through scalp tissue. Certain embodiments described hereinare compatible with irradiation of the brain with light applied to atleast a portion of the scalp or with light applied to at least a portionof the cranium or skull without propagating through the scalp.

FIG. 1 schematically illustrates an example beam delivery apparatus 10in accordance with certain embodiments described herein. The apparatus10 comprises a housing 12, a flexible conduit 14 operatively coupled tothe housing 12, and at least one status indicator 16. In certainembodiments, the apparatus 10 comprises an output optical assembly 20comprising an emission surface 22 through which a light beam 30 isemitted. The output optical assembly 20 is configured to be releasablymechanically coupled to other components of the apparatus 10. The outputoptical assembly 20 can also be configured to be releasably coupled to aposition indicator of a wearable headpiece, as described further herein.

In certain embodiments, the housing 12 is sized to be easily held in onehand (e.g., having a length of approximately 5½ inches). The housing 12of certain embodiments further comprises one or more portions 12 a, 12 bcomprising a biocompatible material since they may contact the operator,the patient, or both. For example, one or more low durometer elastomermaterials (e.g., rubber, polymers, thermoplastic resins) can be used incertain embodiments. The portion 12 a is configured to be grasped by auser's hand during operation of the apparatus 10. The housing 12 ofcertain embodiments is configured so that the emission surface 22 can beheld in position and sequentially moved by hand to irradiate selectedportions of the patient's skin. In certain embodiments, the housing 12comprises one or more recesses or protrusions which facilitate thehousing 12 being gripped by the user. In certain embodiments, thehousing 12 is configured to be placed on a testing system to measure ormonitor the operative parameters of the apparatus 10. The housing 12 ofcertain such embodiments comprises an alignment rib 12 c configured toprovide a registration protrusion which mates with a correspondingregistration recess on the testing system to facilitate proper alignmentof the emission surface 22 with the testing system. The housing 12 ofcertain embodiments comprises two or more portions (e.g., 2-piece casturethane with 60 A overmolding or 3-piece Lustran® with thermoplasticelastomer overmolding) which fit together to form a shell in which otheroperative components are held. In certain embodiments, the light used bythe apparatus 10 can cause eye damage if viewed by an individual. Insuch embodiments, the apparatus 10 can be configured to provide eyeprotection so as to avoid viewing of the light by individuals. Forexample, opaque materials can be used for the housing 12 andappropriately placed to block the light from being viewed directly. Inaddition, interlocks can be provided so that the light source is notactivated unless the apparatus 10 is in place, or other appropriatesafety measures are taken.

In certain embodiments, the housing 12 further comprises a flexible boot17 generally surrounding the portion of the apparatus 10 which isreleasably mounted to the output optical assembly 20. The boot 17 ofcertain embodiments provides a barrier to control, inhibit, prevent,minimize, or reduce contaminants from entering the housing 12. Thus, byvirtue of the boot 17 providing a barrier, the contamination enteringthe housing 12 is lower than it would otherwise be if the boot 17 didnot provide a barrier. Example materials for the flexible boot 17include but are not limited to, rubber or another elastomer.

In certain embodiments, the conduit 14 is configured to operativelycouple the apparatus 10 to various control, power, and cooling systemsthat are spaced from the housing 12. In certain embodiments, the conduit14 comprises at least one optical fiber configured to transmit lightfrom a light source to the apparatus 10 to be emitted from the emissionsurface 22. In certain embodiments, the conduit 14 further comprises oneor more electrically conductive wires (e.g., one 20-conductor cable,four 6-conductor cables, ground braid) configured to transmit signalsbetween the apparatus 10 (e.g., trigger switches or temperature sensorswithin the apparatus 10) and a control system spaced from the apparatus10 and/or to provide electrical power to the apparatus 10 (e.g., for athermoelectric cooler) from a power system. In still other embodiments,the apparatus 10 comprises a power source (e.g., a battery). In certainembodiments, the conduit 14 comprises one or more coolant tubes (e.g.,0.125-inch inner diameter) configured to have a coolant (e.g., liquid orgas) flow to the apparatus 10 from a cooling system. In certainembodiments, the conduit 14 comprises one or more connectors which aremechanically coupled to one or more corresponding connectors within thehousing 12. For example, the conduit 14 can comprise an SMA connector atan end of the optical fiber which is mechanically coupled to acorresponding SMA mount within the housing 12.

In certain embodiments, the conduit 14 comprises a protective sheatharound the one or more fibers, wires, and tubes of the conduit 14. Theprotective sheath of certain embodiments controls, inhibits, prevents,minimizes, or reduces light from exiting the conduit 14 in the event ofa failure of the at least one optical fiber. Thus, by virtue of havingthe sheath, the light exiting the conduit 14 upon fiber failure is lowerthan it would otherwise be without the sheath. In certain embodiments,the protective sheath comprises a strain relief apparatus having aplurality of rigid segments (e.g., stainless steel), with each segmenthaving a generally cylindrical tubular shape and a longitudinal axis.Each segment is articulately coupled to neighboring segments such thatan angle between the longitudinal axes of neighboring segments islimited to be less than a predetermined angle. In certain embodiments,the protective sheath allows the conduit 14 to be moved and to bend, butadvantageously limits the radius of curvature of the bend to besufficiently large to avoid breaking the one or more fibers, wires, ortubes therein. In certain embodiments, the sheath comprises a flexiblecompression spring (e.g., 4 inches in length) to provide bend reliefand/or a tension line to provide strain relief.

In certain embodiments, the at least one status indicator 16 comprisesone, two, or more light-emitting diodes (LEDs) which are lit to visuallyprovide the user with information regarding the status of the apparatus10. For example, the at least one status indicator 16 can be used incertain embodiments to indicate when the laser source is ready to lasepending engagement of the trigger. In certain embodiments, the LEDs canbe lit to show different colors depending on whether the optical power,electrical power, or coolant flow being provided to the apparatus 10 aresufficient for operation of the apparatus 10. In certain embodiments,the at least one status indicator 16 provides information regardingwhether the output optical assembly 20 is properly mounted to theapparatus 10. Other types of status indicators (e.g., flags, soundalarms) are also compatible with certain embodiments described herein.

FIG. 2A schematically illustrates a cross-sectional view of an exampleoutput optical assembly 20 in accordance with certain embodimentsdescribed herein. FIG. 2B schematically illustrates another exampleoutput optical assembly 20 in accordance with certain embodimentsdescribed herein. The output optical assembly 20 comprises an opticalelement 23 comprising the emission surface 22 and a surface 24 facinggenerally away from the emission surface 22. As used herein, the term“element” is used in its broadest sense, including, but not limited to,as a reference to a constituent or distinct part of a composite device.The output optical assembly 20 further comprises a thermal conduit 25 inthermal communication with the optical element 23 (e.g., with a portionof the surface 24). The thermal conduit 25 comprises at least onesurface 26 configured to be in thermal communication with at least oneheat dissipating surface of the apparatus 10 (e.g., a surface of acooling mechanism). The output optical assembly 20 further comprises acoupling portion 27 (e.g., spring-loaded 3-pin bayonet mount or 4-pinbayonet mount) configured to be releasably attached and detached fromthe housing 12. In certain embodiments, the output optical assembly 20comprises one or more springs which provide a sufficient force on the atleast one surface 26 towards the at least one heat dissipating surfaceof the apparatus 10 to have the desired thermal conductivity between thetwo. Various examples of output optical assemblies 20 compatible withcertain embodiments described herein are described more fully in U.S.patent application Ser. No. 12/233,498, which is incorporated in itsentirety by reference herein.

In certain embodiments, the output optical assembly 20 is configured tobe placed in thermal communication with the patient's scalp or skull(e.g., the optical element 23 is configured to contact the patient'sscalp or skull or is configured to be spaced from the patient's scalp orskull but to contact a thermally conductive material in contact with thepatient's scalp or skull). In certain embodiments in which the outputoptical assembly 20 is cooled, the output optical assembly 20 cools atleast a portion of the patient's scalp or skull (e.g., the portion ofthe scalp or skull being irradiated). Thus, in certain embodiments, theoutput optical assembly 20 is adapted to control, inhibit, prevent,minimize, or reduce temperature increases at the scalp or skull causedby the light. Thus, by virtue of the output optical assembly 20 coolingthe portion of the patient's scalp or skull being irradiated, thetemperature of the irradiated portion of the patient's scalp or skull islower than it would otherwise be if the output optical assembly 20 didnot cool the irradiated portion of the scalp or skull. For example, bycooling the irradiated portion of the patient's scalp or skull using theoutput optical assembly 20, the temperature of the irradiated portion ofthe patient's scalp or skull can be higher than the temperature of theportion of the patient's scalp or skull if it were not irradiated, butlower than the temperature of the portion of the patient's scalp orskull if it were irradiated but not cooled. In certain embodiments, thepatient's scalp comprises hair and skin which cover the patient's skull.In other embodiments, at least a portion of the hair is removed prior tothe phototherapy treatment, so that the output optical assembly 20substantially contacts the skin of the scalp.

The optical element 23 of certain embodiments is thermally conductive,and optically transmissive at wavelengths which are transmitted by skin.For example, in certain embodiments, the thermal conductivity of theoptical element 23 is sufficient to remove heat from the irradiatedportion of the patient's scalp or skull, and the optical transmissivityof the optical element 23, at wavelengths selected to provide thedesired irradiance at a target region of the brain, is sufficient toallow the desired irradiance of light to propagate through the opticalelement 23 to irradiate the patient's scalp or skull. In certainembodiments, the optical element 23 comprises a rigid material, while incertain other embodiments, the optical element 23 comprises a lowdurometer, thermally conductive, optically transmissive material (e.g.,a flexible bag or container filled with a thermally conductive,optically transmissive liquid such as water). Example rigid materialsfor the optical element 23 include, but are not limited to, sapphire,diamond, calcium fluoride, and zinc selenide. In certain embodiments,the optical element 23 has an emission surface 22 configured to facegenerally towards the surface to be irradiated (e.g., the patient'sscalp or skull). In certain embodiments, the emission surface 22 isadapted to be placed in contact with either the irradiated surface orwith a substantially optically transmissive and substantially thermallyconductive material which is in contact with the irradiated surface. Theemission surface 22 of certain embodiments is configured to be inthermal communication with the surface to be irradiated by the lightbeam emitted from the emission surface 22. In certain such embodiments,the thermal conductivity of the optical element 23 is sufficiently highto allow heat to flow from the emission surface 22 to the thermalconduit 25 at a sufficient rate to control, inhibit, prevent, minimize,or reduce damage to the skin or discomfort to the patient from excessiveheating of the skin due to the irradiation. Thus, by virtue of thethermal conductivity of the optical element 23, any damage to the skinor discomfort to the patient can be lower than it would otherwise be ifthe optical element 23 did not have a sufficiently high thermalconductivity. For example, the damage to the skin or discomfort to thepatient can be higher than it would be if the portion of the patient'sscalp were not irradiated, but the damage to the skin or discomfort tothe patient would be lower than it would be if the optical element 23did not have a sufficiently high thermal conductivity.

In certain embodiments, the optical element 23 has a thermalconductivity of at least approximately 10 watts/meter-K. In certainother embodiments, the thermal conductivity of the optical element 23 isat least approximately 15 watts/meter-K. Examples of materials for theoptical element 23 in accordance with certain embodiments describedherein include, but are not limited to, sapphire which has a thermalconductivity of approximately 23.1 watts/meter-K, and diamond which hasa thermal conductivity between approximately 895 watts/meter-K andapproximately 2300 watts/meter-K.

In certain embodiments, the emission surface 22 is adapted to conform tothe curvature of the scalp or skull. The emission surface 22 of certainembodiments is concave (e.g., generally spherical with a radius ofcurvature of about 100 millimeters). By fitting to the curvature of thescalp or skull, the emission surface 22 advantageously controls,inhibits, prevents, minimizes, or reduces temperature increases at thescalp or skull that would otherwise result from air-filled gaps betweenthe emission surface 22 and the scalp or skull. Thus, by virtue of theemission surface 22 fitting to the curvature of the portion of thepatient's scalp or skull being irradiated, the temperature of theirradiated portion of the patient's scalp or skull is lower than itwould otherwise be if the emission surface 22 did not fit to thecurvature of the irradiated portion of the scalp or skull. For example,by fitting the emission surface 22 to the curvature of the irradiatedportion of the patient's scalp or skull, the temperature of theirradiated portion of the patient's scalp or skull can be higher thanthe temperature of the portion of the patient's scalp or skull if itwere not irradiated, but lower than the temperature of the portion ofthe patient's scalp or skull if it were irradiated but the emissionsurface 22 did not fit to the portion of the patient's scalp or skull.The existence of air gaps between the emission surface 22 and the scalpor skull can reduce the thermal conductivity between the emissionsurface 22 and the scalp or skull, thereby increasing the probability ofheating the scalp or skull by the irradiation.

In addition, the refractive-index mismatches between such an air gap andthe emission surface 22 and/or the scalp or skull can cause a portion ofthe light propagating toward the scalp or skull to be reflected awayfrom the scalp or skull. In certain embodiments, the emission surface 22is placed in contact with the skin of the scalp or skull so as toadvantageously substantially reduce air gaps between the emissionsurface 22 and the scalp or skull in the optical path of the light. Incertain other embodiments in which an intervening material (e.g., asubstantially optically transmissive and substantially thermallyconductive gel) is in contact with the scalp or skull and with theemission surface 22, the emission surface 22 is placed in contact withthe intervening material so as to advantageously avoid creating air gapsbetween the emission surface 22 and the intervening material or betweenthe intervening material and the scalp or skull. In certain embodiments,the intervening material has a refractive index at a wavelength of lightimpinging the scalp which substantially matches the refractive index ofthe scalp (e.g., about 1.3), thereby reducing anyindex-mismatch-generated back reflections between the emission surface22 and the scalp. Examples of materials compatible with certain suchembodiments described herein include, but are not limited to, glycerol,water, and silica gels. Example index-matching gels include, but are notlimited to, those available from Nye Lubricants, Inc. of Fairhaven,Mass.

In certain embodiments, the emission surface 22 comprises one or moreoptical coatings, films, layers, membranes, etc. in the optical path ofthe transmitted light which are adapted to reduce back reflections. Byreducing back reflections, the emission surface 22 increases the amountof light transmitted to the brain and reduces the need to use higherirradiances which may otherwise create temperature increases at thescalp or skull.

In certain embodiments, the output optical assembly 20 is adapted todiffuse the light prior to reaching the scalp or skull to advantageouslyhomogenize the light beam prior to reaching the emission surface 22.Generally, intervening tissues of the scalp and skull are highlyscattering, which can reduce the impact of non-uniform beam intensitydistributions on the illumination of the patient's cerebral cortex.However, non-uniform beam intensity distributions with substantialinhomogeneities could result in some portions of the patient's scalp orskull being heated more than others (e.g., localized heating where a“hot spot” of the light beam impinges the patient's scalp or skull). Incertain embodiments, the output optical assembly 20 advantageouslyhomogenizes the light beam to have a non-uniformity less thanapproximately 3 millimeters. FIGS. 3A and 3B schematically illustratethe diffusive effect on the light by the output optical assembly 20. Anexample energy density profile of the light prior to being transmittedthrough the output optical assembly 20, as illustrated by FIG. 3A, ispeaked at a particular emission angle. After being diffused by theoutput optical assembly 20, as illustrated by FIG. 3B, the energydensity profile of the light does not have a substantial peak at anyparticular emission angle, but is substantially evenly distributed amonga range of emission angles. By diffusing the light, the output opticalassembly 20 distributes the light energy substantially evenly over thearea to be illuminated, thereby controlling, inhibiting, preventing,minimizing, or reducing “hot spots” which would otherwise createtemperature increases at the scalp or skull. Thus, by virtue of theoutput optical assembly 20 diffusing the light, the temperature of theirradiated portion of the patient's scalp or skull is lower than itwould otherwise be if the output optical assembly 20 did not diffuse thelight. For example, by diffusing the light using the output opticalassembly 20, the temperature of the irradiated portion of the patient'sscalp or skull can be higher than the temperature of the portion of thepatient's scalp or skull if it were not irradiated, but lower than thetemperature of the portion of the patient's scalp or skull if it wereirradiated but the light were not diffused by the output opticalassembly 20. In addition, by diffusing the light prior to reaching thescalp or skull, the output optical assembly 20 can effectively increasethe spot size of the light impinging the scalp or skull, therebyadvantageously lowering the irradiance at the scalp or skull, asdescribed in U.S. Pat. No. 7,303,578, which is incorporated in itsentirety by reference herein.

In certain embodiments, the output optical assembly 20 providessufficient diffusion of the light such that the irradiance of the lightis less than a maximum tolerable level of the scalp, skull, or brain.For example, the maximum tolerable level of certain embodiments is alevel at which the patient experiences discomfort or pain, while incertain other embodiments, the maximum level is a level at which thepatient's scalp or skull is damaged (e.g., burned). In certain otherembodiments, the output optical assembly 20 provides sufficientdiffusion of the light such that the irradiance of the light equals atherapeutic value at the subdermal target tissue. The output opticalassembly 20 can comprise example diffusers including, but are notlimited to, holographic diffusers such as those available from PhysicalOptics Corp. of Torrance, Calif. and Display Optics P/N SN1333 fromReflexite Corp. of Avon, Conn.

In certain embodiments, the output optical assembly 20 provides areusable interface between the apparatus 10 and the patient's scalp orskull. In such embodiments, the output optical assembly 20 can becleaned or sterilized between uses of the apparatus 10, particularlybetween uses by different patients. In other embodiments, the outputoptical assembly 20 provides a disposable and replaceable interfacebetween the apparatus 10 and the patient's scalp or skull. By usingpre-sterilized and pre-packaged replaceable interfaces, certainembodiments can advantageously provide sterilized interfaces withoutundergoing cleaning or sterilization processing immediately before use.

In certain embodiments, the output optical assembly 20 is adapted toapply pressure to at least an irradiated portion of the scalp. Forexample, the output optical assembly 20 is capable of applying pressureto at least an irradiated portion of the scalp upon a force beingapplied to the apparatus 10 (e.g., by an operator of the apparatus 10pressing the apparatus 10 against the patient's scalp by hand or bymechanical means to generate force, such as weights, springs, tensionstraps). By applying sufficient pressure, the output optical assembly 20can blanch the portion of the scalp by forcing at least some blood outthe optical path of the light energy. (For a general discussion of skinblanching, see, e.g., A. C. Burton et al., “Relation Between BloodPressure and Flow in the Human Forearm,” J. Appl. Physiology, Vol. 4,No. 5, pp. 329-339 (1951); A. Matas et al., “Eliminating the Issue ofSkin Color in Assessment of the Blanch Response,” Adv. in Skin & WoundCare, Vol. 14(4, part 1 of 2), pp. 180-188 (July/August 2001); J.Niitsuma et al., “Experimental study of decubitus ulcer formation in therabbit ear lobe,” J. of Rehab. Res. and Dev., Vol. 40, No. 1, pp. 67-72(January/February 2003).) The blood removal resulting from the pressureapplied by the output optical assembly 20 to the scalp decreases thecorresponding absorption of the light energy by blood in the scalp. As aresult, temperature increases due to absorption of the light energy byblood at the scalp are reduced. As a further result, the fraction of thelight energy transmitted to the subdermal target tissue of the brain isincreased. In certain embodiments, a pressure of at least 0.1 pound persquare inch is used to blanch the irradiated portion of the scalp, whilein certain other embodiments, a pressure of at least one pound persquare inch is used to blanch the irradiated portion of the scalp. Incertain embodiments, a pressure of at least about two pounds per squareinch is used to blanch the irradiated portion of the scalp. Other valuesor ranges of pressures for blanching the irradiated portion of the scalpare also compatible with certain embodiments described herein. Themaximum pressure used to blanch the irradiated portion of the scalp islimited in certain embodiments by patient comfort levels and tissuedamage levels.

FIGS. 4A and 4B schematically illustrate cross-sectional views of twoexample beam delivery apparatuses 10 in accordance with certainembodiments described herein. In FIGS. 4A and 4B, the apparatus 10comprises an output optical assembly 20 having an emission surface 22and releasably operatively coupled to the other components of theapparatus 10. The apparatus 10 comprises an optical fiber 40, a fiberalignment mechanism 50 operatively coupled to the optical fiber 40, amirror 60 in optical communication with the optical fiber 40, and awindow 70 in optical communication with the mirror 60. During operationof the apparatus 10, light 30 from the optical fiber 40 propagates tothe mirror 60 and is reflected by the mirror 60 to propagate through thewindow 70. The light 30 transmitted through the window 70 propagatesthrough the output optical assembly 20 along a first optical path and isemitted from the emission surface 22. In certain embodiments, theapparatus 10 comprises additional optical elements (e.g., lenses,diffusers, and/or waveguides) which transmit at least a portion of thelight received via the optical fiber 40 to the emission surface 22. Incertain such embodiments, the additional optical elements of theapparatus 10 shape, format, or otherwise modify the light such that thelight beam emitted from the emission surface 22 has the desired beamintensity profile.

In certain embodiments, the optical fiber 40 comprises a step-index orgraded-index optical fiber. The optical fiber 40 of certain embodimentsis single-mode, while in certain other embodiments, the optical fiber ismultimode. An example optical fiber 40 compatible with certainembodiments described herein has a 1000-micron diameter and a numericalaperture of approximately 0.22.

FIG. 5 schematically illustrates an example fiber alignment mechanism 50in accordance with certain embodiments described herein. In certainembodiments, the fiber alignment mechanism 50 is mechanically coupled toa portion of the optical fiber 40 and is configured to allow adjustmentsof the position, tilt, or both of the end of the optical fiber 40 fromwhich the light is emitted. In certain embodiments, the fiber alignmentmechanism 50 provides an adjustment range of at least ±5 degrees. Thefiber alignment mechanism 50 of FIG. 5 comprises a connector 52 (e.g.,SMA connector) mechanically coupled to the optical fiber 40, a plate 54(e.g., a kinematic tilt stage) mechanically coupled to the connector 52,and a plurality of adjustment screws 56 (e.g., 80 turns per inch or 100turns per inch) adjustably coupled to the plate 54. By turning theadjustment screws 56, a distance between a portion of the plate 54 and acorresponding portion of a reference structure 58 can be adjusted. Incertain embodiments, the fiber alignment mechanism 50 comprises one ormore locking screws 59 configured to be tightened so as to fix the plate54 at a position, orientation, or both relative to the referencestructure 58. Other configurations of the fiber alignment mechanism 50are also compatible with certain embodiments described herein.

FIG. 6 schematically illustrates an example mirror 60 compatible withcertain embodiments described herein. In certain embodiments, the mirror60 is substantially reflective of light emitted from the optical fiber40 to reflect the light through a non-zero angle (e.g., 90 degrees). Themirror 60 of certain embodiments comprises a glass substrate coated onat least one side by a metal (e.g., gold or aluminum). Examples ofmirrors 60 compatible with certain embodiments described herein include,but are not limited to, a flat, generally planar glass mirror (e.g.,NT43-886 available from Edmund Optics Inc. of Barrington, N.J.). Themirror 60 of certain embodiments can be configured to have an opticalpower (e.g., the mirror 60 can be concave) and be adapted to shape,format, or otherwise modify the light to produce a desired beamintensity profile. In certain embodiments, the mirror 60 is bondedaround its perimeter by an adhesive (e.g., OP-29 adhesive available fromDymax Corp. of Torrington, Conn.) to a support structure 62.

In certain embodiments, the mirror 60 is partially transmissive of lightemitted from the optical fiber 40. In certain such embodiments, thesupport structure 62 comprises an opening and the apparatus 10 comprisesat least one light sensor 64 positioned to receive light transmittedthrough the mirror 60 and the opening of the support structure 62. Theat least one light sensor 64 is configured to generate a signalindicative of the intensity of the received light, thereby providing ameasure of the intensity of the light reaching the mirror 60. Examplesof light sensors 64 compatible with certain embodiments described hereininclude, but are not limited to, OPT101 photodiode available from TexasInstruments of Dallas, Tex. In certain embodiments, a plurality of lightsensors 64 are used to provide operational redundancy to confirm thatlight with a sufficient intensity for operation of the apparatus 10 isbeing provided by the optical fiber 40. In certain embodiments, adiffuser 66 is positioned to diffuse the light transmitted through themirror 60 before the light impinges the light sensor 64. In certainembodiments, the light sensor 64 is protected from stray light by anopaque shroud 68 generally surrounding the light sensor 64.

In certain embodiments, the window 70 is substantially transmissive toinfrared radiation. Example windows 70 compatible with certainembodiments described herein include, but are not limited to, a flat,generally planar CaF₂ window (e.g., TechSpec® calcium fluoride windowavailable from Edmund Optics Inc. of Barrington, N.J.).

In certain embodiments, the window 70 at least partially bounds a regionwithin the apparatus 10 which contains the mirror 60. The window 70 ofcertain such embodiments substantially seals the region againstcontaminants (e.g., dust, debris) from entering the region from outsidethe region. For example, when the output optical assembly 20 isdecoupled from the apparatus 10, the window 70 controls, inhibits,prevents, minimizes, or reduces contaminants entering the region. Thus,by virtue of the window 70 substantially sealing the region, thecontamination of the region is lower than it would otherwise be if thewindow 70 did not substantially seal the region.

FIG. 7 schematically illustrates an example first optical path 32 oflight 30 emitted from the optical fiber 40 in accordance with certainembodiments described herein. The diverging light 30 exiting the opticalfiber 40 propagates along the first optical path 32 towards the mirror60. The light 30 is reflected by the mirror 60 and propagates along thefirst optical path 32 through the window 70, impinges or is received bythe surface 24 of the optical element 23, and is emitted from theemission surface 22 towards the surface to be irradiated. In certainembodiments, the mirror 60 reflects the light 30 through an angle ofabout 90 degrees. In certain embodiments, the mirror 60 is about 2.3inches from the face of the optical fiber 40 and the first optical path32 is about 4.55 inches in length from the fiber output face to theemission surface 22 of the optical element 23.

In certain embodiments, the apparatus 10 further comprises a sensor 80spaced from the output optical assembly 20. FIG. 8 schematicallyillustrates an example second optical path 82 of radiation 84 receivedby the sensor 80. The sensor 80 is positioned to receive the radiation84 from the output optical assembly 20 propagating through the outputoptical assembly 20 along the second optical path 82. The first opticalpath 32 and the second optical path 82 have a non-zero angletherebetween. In certain embodiments, the second optical path 82 isco-planar with the first optical path 32, while in certain otherembodiments, the first optical path 32 and the second optical path 82are non-co-planar with one another. The sensor 80 of certain embodimentsreceives radiation 84 propagating along the second optical path 82 fromat least a portion of the surface 24 of the optical element 23 duringoperation of the apparatus 10.

The sensor 80 of certain embodiments comprises a temperature sensor(e.g., thermopile) configured to receive infrared radiation from aregion and to generate a signal indicative of the temperature of theregion. Examples of temperature sensors compatible with certainembodiments described herein include, but are not limited to, DX-0496thermopile available from Dexter Research Center, Inc. of Dexter, Mich.In certain embodiments, the field-of-view of the sensor 80 comprises anarea of about 0.26 square inches of the surface 24 spaced from thethermal conduit 25 (e.g., by a distance between 0.05 inch and 0.3 inch).In certain other embodiments, the field-of-view of the sensor 80comprises an area of about 0.57 square inches of the surface 24.

In certain embodiments, the sensor 80 is responsive to the receivedradiation 84 by generating a signal indicative of a temperature of theskin or of a portion of the output optical assembly 20 (e.g., theoptical element 23). In certain such embodiments, the apparatus 10further comprises a controller configured to receive the signal from thesensor 80 and to cause a warning to be generated, to turn off a sourceof the light propagating along the first optical path 32, or both inresponse to the signal indicating that the temperature is above apredetermined threshold temperature (e.g., 42 degrees Celsius).

The sensor 80 of certain embodiments is not in thermal communicationwith the output optical assembly 20. As shown in FIG. 8, theinfrared-transmissive window 70 is between the sensor 80 and the outputoptical assembly 20. The light 30 propagating along the first opticalpath 32 and the infrared radiation 84 propagating along the secondoptical path 82 both propagate through the window 70. In certainembodiments, the sensor 80 is wholly or at least partially within aregion of the housing 12 at least partially bound, and substantiallysealed by the window 70 against contaminants from entering the regionfrom outside the region.

In certain embodiments, the apparatus 10 is adapted to cool theirradiated portion of the scalp or skull by removing heat from the scalpor skull so as to control, inhibit, prevent, minimize, or reducetemperature increases at the scalp or skull. Thus, by virtue of theapparatus 10 cooling the irradiated portion of the patient's scalp orskull, the temperature of the irradiated portion of the patient's scalpor skull is lower than it would otherwise be if the apparatus 10 did notcool the irradiated portion of the scalp or skull. For example, bycooling the irradiated portion of the patient's scalp or skull using theapparatus 10, the temperature of the irradiated portion of the patient'sscalp or skull can be higher than the temperature of the portion of thepatient's scalp or skull if it were not irradiated, but lower than thetemperature of the portion of the patient's scalp or skull if it wereirradiated but not cooled. Referring to FIGS. 4A and 4B, in certainembodiments, the apparatus 10 comprises a thermoelectric assembly 90 anda heat sink 100 in thermal communication with the thermoelectricassembly 90. In certain embodiments, the thermoelectric assembly 90actively cools the patient's scalp or skull via the output opticalassembly 20, thereby advantageously avoiding large temperature gradientsat the patient's scalp or skull which would otherwise cause discomfortto the patient. In certain embodiments, the apparatus 10 furthercomprises one or more temperature sensors (e.g., thermocouples,thermistors) which generate electrical signals indicative of thetemperature of the thermoelectric assembly 90.

In certain embodiments, the thermoelectric assembly 90 comprises atleast one thermoelectric element 91 and a thermal conduit 92. The atleast one thermoelectric element 91 of the thermoelectric assembly 90 isresponsive to an electric current applied to the thermoelectric assembly90 by cooling at least a first surface 93 of the thermoelectric assembly90 and heating at least a second surface 94 of the thermoelectricassembly 90. The thermoelectric assembly 90 is configured to bereleasably mechanically coupled to the output optical assembly 20 so asto have the first surface 93 in thermal communication with the outputoptical assembly 20. In certain embodiments, the first surface 93comprises a surface of the thermal conduit 92 and the second surface 94comprises a surface of the thermoelectric element 91.

FIG. 9A schematically illustrates an example thermoelectric element 91and FIG. 9B schematically illustrates two views of an example thermalconduit 92 in accordance with certain embodiments described herein. FIG.10A schematically illustrates another example thermoelectric element 91and FIG. 10B schematically illustrates two views of another examplethermal conduit 92 in accordance with certain embodiments describedherein. The thermoelectric element 91 has a surface 95 configured to bein thermal communication with a corresponding surface 96 of the thermalconduit 92 (e.g., by a thermally conductive adhesive). Upon applicationof an electric current to the thermoelectric element 91, the secondsurface 94 is heated and the surface 95 is cooled, thereby cooling thefirst surface 93. In certain such embodiments, the first surface 93serves as at least one heat dissipating surface of the apparatus 10configured to be in thermal communication with the at least one surface26 of the thermal conduit 25 of the output optical assembly 20 (e.g., bycontacting or mating so as to provide a thermally conductive connectionbetween the thermoelectric assembly 26 and the output optical assembly20). By having the thermally conductive output optical assembly 20 inthermal communication with the thermoelectric assembly 90, certainembodiments advantageously provide a conduit for heat conduction awayfrom the treatment site (e.g., the skin). In certain embodiments, theoutput optical assembly 20 is pressed against the patient's skin andtransfers heat away from the treatment site.

Examples of thermoelectric elements 91 compatible with certainembodiments described herein include, but are not limited to, DT12-6,Q_(max)=60 W, square thermoelectric element available from MarlowIndustries of Dallas, Tex., and Q_(max)=45 W toroidal- or donut-shapedthermoelectric element from Ferrotec Corp. of Bedford, N.H. In certainembodiments, the thermoelectric element 91 removes heat from the outputoptical assembly 20 at a rate in a range of about 0.1 Watt to about 5Watts or in a range of about 1 Watt to about 3 Watts. Exampletemperature controllers for operating the thermoelectric assembly 90 inaccordance with certain embodiments described herein include, but arenot limited to, MPT-5000 available from Wavelength Electronics, Inc. ofBozeman, Mont. Example materials for the thermal conduit 92 compatiblewith certain embodiments described herein include, but are not limitedto, aluminum and copper. The thermal conduit 92 of certain embodimentshas a thermal mass in a range of about 30 grams to about 70 grams, andhas a thermal length between surface 93 and surface 96 in a range ofabout 0.5 inch to about 3.5 inches.

In certain embodiments, the thermoelectric assembly 90 generallysurrounds a first region 97, wherein, during operation of the apparatus10, light irradiating a portion of the patient's skin propagates throughthe first region 97. As shown in FIGS. 9B and 10B, in certainembodiments, the first region 97 comprises an aperture through thethermal conduit 92. As shown in FIG. 10B, the first region 97 in certainembodiments further comprises an aperture through the thermoelectricelement 91. In certain embodiments, the thermoelectric assembly 90comprises a plurality of thermoelectric elements 91 which are spacedfrom one another and are distributed to generally surround the firstregion 97. As used herein, the term “generally surrounds” has itsbroadest reasonable interpretation, including but not limited to,encircles or extends around at least one margin of the region, or beingdistributed around at least one margin of the region with one or moregaps along the at least one margin.

FIG. 11A schematically illustrates a cross-sectional view of an exampleheat sink 100 and FIG. 11B schematically illustrates another exampleheat sink 100 in accordance with certain embodiments described herein.The heat sink 100 comprises an inlet 101, an outlet 102, and a fluidconduit 103 in fluid communication with the inlet 101 and the outlet102. The inlet 101 and the outlet 102 of certain embodiments comprisestainless steel barbs configured to be connected to tubes (e.g., usingnylon or stainless steel hose barb locks, clamps, or crimps) whichprovide a coolant (e.g., water, air, glycerol) to flow through the fluidconduit 103 and to remove heat from the fluid conduit 103. In certainembodiments, the coolant is provided by a chiller or other heat transferdevice which cools the coolant prior to its being supplied to the heatsink 100.

The example heat sink 100 of FIG. 11A is machined from an aluminum blockand has a recess 104 in which the thermoelectric assembly 90 is placedto provide thermal communication between the heat sink 100 and thesecond surface 94 of the thermoelectric assembly 90. The example heatsink 100 of FIG. 11B comprises a first portion 105 and a second portion106 which fit together to form the coolant conduit 103. In certainembodiments, a thermally conductive adhesive (e.g., EP1200 thermaladhesive available from Resinlab, LLC of Germantown, Wis., with a0.005-inch stainless steel wire to set the bondline) is used to bond thethermoelectric assembly 90 and the heat sink 100 together in thermalcommunication with one another.

The output optical assembly 20 comprises a thermally conductive thermalconduit 25 having at least one surface 26 configured to be in thermalcommunication with the first surface of the thermoelectric assembly 90.As shown in FIGS. 2A and 2B, the thermal conduit 25 generally surroundsa second region 28. During operation of the apparatus 10, the lightpropagates through the first region 97, the second region 28, and theoptical element 23. In certain embodiments, the heat sink 100 generallysurrounds a third region 107, as schematically illustrated by FIG. 11B.During operation of the apparatus 10 in certain such embodiments, thelight propagates through the third region 107, the first region 97, thesecond region 28, and the optical element 23.

FIGS. 12A and 12B schematically illustrate two example configurations ofthe window 70 with the thermoelectric assembly 90. In certainembodiments, the window 70 is in thermal communication with at least aportion of the thermoelectric assembly 90 (e.g., bonded to a recess inthe thermal conduit 92, as shown in FIG. 12A, using OP-29 adhesiveavailable from Dymax Corp. of Torrington, Conn.). In certainembodiments, the window 70 is in thermal communication with at least aportion of the heat sink 100 (e.g., retained by an o-ring in the heatsink 100), as shown in FIG. 12B. In certain embodiments, the window 70is not in thermal communication with either the thermoelectric assembly90 or the heat sink 100.

FIG. 13A schematically illustrates an example chassis 110 for supportingthe various components of the beam delivery apparatus 10 within thehousing 12 in accordance with certain embodiments described herein. Thechassis 110 of FIG. 13A comprises a single unitary or monolithic piecewhich is machined to provide various surfaces and holes used to mountthe various components of the beam delivery apparatus 10. FIG. 13Bschematically illustrates another example chassis 110 in accordance withcertain embodiments described herein. The chassis 110 of FIG. 13Bcomprises a plurality of portions which are bolted or pinned together.

FIG. 14A schematically illustrates a cross-sectional view of an exampleconfiguration of the chassis 110 and the housing 12 in accordance withcertain embodiments described herein. The chassis 110 of certainembodiments is electrically connected to ground, while in certain otherembodiments, the chassis 110 is electrically insulated from ground(e.g., floating). In certain embodiments, the chassis 110 is configuredto move relative to the housing 12. For example, the chassis 110 and thehousing 12 are mechanically coupled together by a pivot 112, asschematically illustrated by FIG. 14A. The optical fiber 40, fiberadjustment apparatus 50, mirror 60, window 70, sensor 80, and heat sink100 are each mechanically coupled to the chassis 110. The output opticalassembly 20 is also mechanically coupled to the chassis 110 via thethermoelectric assembly 90 and the heat sink 100.

For the configuration of FIG. 14A, the emission surface 22 of the outputoptical assembly 20 is placed in thermal communication (e.g., incontact) with the patient's scalp or skull by a user pressing thehousing 12 towards the scalp or skull. The pivot 112 allows the chassis110 to rotate about the pivot 112 relative to the housing 12 (e.g., byan angle between 1 and 2 degrees, or about 1.75 degrees) such that theemission surface 22 moves towards the housing 12 (e.g., by a distance of0.05-0.3 inch, or about 0.1 inch). In certain such embodiments, thismovement of the chassis 110, as well as of the fiber adjustmentapparatus 50 and the optical fiber 40, results in a flexing of a portionof the optical fiber 40 (e.g., in proximity to the coupling between thehousing 12 and the conduit 14).

This flexing of the optical fiber 40 can be undesirable in certaincircumstances, such as when the optical fiber 40 or its connection tothe fiber adjustment apparatus 50 is fragile and prone to breakage orfailure due to repeated flexing. FIGS. 14B and 14C schematicallyillustrate another example configuration of the chassis 110 and thehousing 12 in accordance with certain embodiments described herein. Thechassis 110 comprises a first chassis element 120 and a second chassiselement 122 mechanically coupled to the first chassis element 120 suchthat the first chassis element 120 and the second chassis element 122can move relative to one another. For example, in certain embodiments,the apparatus 10 further comprises a hinge 124 (e.g., a pivot orflexible portion) about which the first chassis element 120 and thesecond chassis element 122 are configured to deflect relative to oneanother.

In certain embodiments, the first chassis element 120 is mechanicallycoupled to the housing 12, and the optical fiber 40, fiber adjustmentapparatus 50, mirror 60, and sensor 80 (each shown in dotted lines inFIG. 14C) are mechanically coupled to the first chassis element 120. Thesecond chassis element 122 is mechanically coupled to the window 70,thermoelectric assembly 90, and the heat sink 100 (each shown in dottedlines in FIG. 14C). The output optical assembly 20 is also mechanicallycoupled to the second chassis element 122 via the thermoelectricassembly 90 and the heat sink 100. Thus, in certain such embodiments, afirst portion of the apparatus 10 comprises the housing 12, firstchassis element 120, optical fiber 40, fiber adjustment apparatus 50,mirror 60, and sensor 80, and a second portion of the apparatus 10comprises the second chassis element 122, window 70, thermoelectricassembly 90, heat sink 100, and output optical assembly 20. The secondportion is mechanically coupled to the first portion and is in opticalcommunication with the first portion. The second portion is configuredto be placed in thermal communication with the patient's skin such thatthe light from the first portion propagates through the second portionduring operation of the apparatus 10. The first portion and the secondportion are configured to move relative to one another in response tothe second portion being placed in thermal communication with thepatient's skin.

In certain embodiments, the second portion comprises the output opticalassembly 20 and the first portion and the second portion are configuredto deflect relative to one another by a non-zero angle. In certainembodiments, this deflection occurs upon the output optical assembly 20applying a pressure to a portion of the patient's scalp sufficient to atleast partially blanch the portion of the patient's scalp. In certainembodiments, this deflection occurs upon the output optical assembly 20being placed in thermal communication with the patient's scalp or skull.In certain embodiments, the apparatus 10 further comprises a springmechanically coupled to the first portion and the second portion. Thespring provides a restoring force in response to movement of the firstportion and the second portion relative to one another.

For the configuration of FIGS. 14B and 14C, the emission surface 22 ofthe output optical assembly 20 is placed in thermal communication (e.g.,in contact) with the patient's scalp or skull by a user pressing thehousing 12 towards the scalp or skull. The hinge 124 allows the secondportion (e.g., including the second chassis element 122) to rotate aboutthe hinge 124 relative to the first portion (e.g., including the firstchassis element 120). This rotation can be by an angle between 1 and 3degrees, or about 2.3 degrees) such that the emission surface 22 movestowards the housing 12 (e.g., by a distance of 0.05-0.3 inch, or about0.08 inch). In certain such embodiments in which the first portioncomprises the optical fiber 40, deflection of the first portion and thesecond portion relative to one another controls, inhibits, prevents,minimizes, or reduces flexing or movement of the optical fiber 40 (e.g.,to control, inhibit, prevent, minimize, or reduce damage to the opticalfiber 40). Thus, by virtue of the movement of the first and secondportions relative to one another, the flexing, movement, or damage ofthe optical fiber 40 is lower than it would otherwise be if the firstand second portions did not move relative to one another.

In certain embodiments, the relative movement of the output opticalassembly 20 and the mirror 60 can result in the light beam 30 being atleast partially occluded or “clipped” by the thermal conduit 25 of theoutput optical assembly 20. For example, for a light beam diameter of 30millimeters, the light beam 30 is not clipped by the thermal conduit 25.For larger light beam diameters, the light beam 30 is partially occludedby the thermal conduit 25. For a light beam diameter of 31 millimeters,about 0.02% of the light beam area is occluded, and for 32 millimeters,about 1.56% of the light beam area is occluded, resulting in anestimated power loss of less than about 0.08%.

In certain embodiments, the apparatus 10 further comprises a sensor 130configured to detect movement of the first portion and the secondportion relative to one another (e.g., movement of the first chassiselement 120 and the second chassis element 122 relative to one another).The sensor 130 is configured to transmit a signal to a controllerconfigured to receive the signal and to control a light source inresponse to the signal, where the light source is configured to generatethe light used by the apparatus 10 irradiate the patient's scalp orskull. In certain embodiments, the sensor 130 transmits the signal tothe controller upon detecting that the movement between the firstportion and the second portion is larger than a predetermined thresholdvalue. In this way, the sensor 130 serves as a trigger switch which isused to trigger the apparatus 10 (e.g., providing the apparatus 10 withlight upon the sensor 130 detecting the predetermined amount of movementbetween the first portion and the second portion indicative of theapparatus 10 being in a condition for use). The trigger switch ofcertain embodiments is actuated by pressing the output optical assembly20 against a surface. The light source providing light to the apparatus10 is responsive to the trigger switch by emitting light only when thetrigger switch is actuated. Therefore, in certain such embodiments, toutilize the apparatus 10, the output optical assembly 20 is pressedagainst the patient's skin, such as described above.

FIGS. 15A and 15B schematically illustrate two states of an examplesensor 130 in accordance with certain embodiments described herein. Thesensor 130 comprises at least one trigger flag 132 mechanically coupledto the first portion (e.g., the housing 12) and at least one opticalswitch 134 mechanically coupled to the second portion (e.g., the secondchassis element 122). For example, the at least one optical switch 134of certain embodiments comprises one, two, or more EE-SX-1035 opticalswitches available from Omron Electronics Components LLC of Schaumburg,Ill. In a first state, the trigger flag 132 is displaced away from asensor light beam which is detected by the optical switch 134. Uponpressing the output optical assembly 20 in thermal communication withthe patient's scalp or skull, the optical switch 134 moves relative tothe trigger flag 132 (e.g., by a distance of about 0.07 inch) such thatthe trigger flag 132 intercepts the sensor light beam such that it is nolonger detected by the optical switch 134. In response to this secondstate, the sensor 130 generates a corresponding signal. In certain otherembodiments, the trigger flag 132 can be positioned to intercept thesensor light beam in the first state and to not intercept the sensorlight beam in the second state.

FIGS. 15C and 15D schematically illustrate two states of another examplesensor 130 in accordance with certain embodiments described herein. Thesensor 130 comprises a reflective element 135 mechanically coupled tothe first portion (e.g., the first chassis element 120) and at least onelight source/detector pair 136 mechanically coupled to the secondportion (e.g., the second chassis element 122). For example, the atleast one light source/detector pair 136 a, 136 b of certain embodimentscomprises one, two, or more QRE1113GR reflective sensors available fromFairchild Semiconductor Corp. of San Jose, Calif. In a first state, thereflective surface 135 is a first distance away from the lightsource/detector pair 136 a, 136 b such that a sensor light beam from thesource 136 a is reflected from the surface 135 but is not detected bythe detector 136 b. Upon pressing the output optical assembly 20 inthermal communication with the patient's scalp or skull, the reflectivesurface 135 moves (e.g., by a distance of about 0.04 inch) to be asecond distance away from the light source/detector pair 136 a, 136 bsuch that the sensor light beam from the source 136 a is reflected fromthe surface 135 and is detected by the detector 136 b. In response tothis second state, the sensor 130 generates a corresponding signal. Incertain embodiments, the sensor 130 further comprises a shroud 137configured to protect the detector 136 b from stray light. In certainother embodiments, the reflective surface 135 can be positioned toreflect the sensor light beam to the detector 136 b in the first stateand to not reflect the sensor light beam to the detector 136 b in thesecond state.

In certain embodiments, the apparatus 10 further comprises an adjustmentmechanism configured to set the predetermined threshold value, to changethe predetermined threshold value, or both. In certain such embodiments,the adjustment mechanism comprises a set screw which changes therelative positions of the two portions of the sensor 130 which moverelative to one another. Certain embodiments further comprise a stopconfigured to limit a range of movement of the first portion and thesecond portion relative to one another.

In certain embodiments, the apparatus 10 comprises a trigger forcespring 140 and a trigger force adjustment mechanism 142. FIGS. 16A and16B schematically illustrate two example configurations of the triggerforce spring 140 and trigger force adjustment mechanism 142 inaccordance with certain embodiments described herein. The trigger forcespring 140 is mechanically coupled to the first portion (e.g., the firstchassis element 120) and the second portion (e.g., the second chassiselement 122) and provides a restoring force when the first portion andthe second portion are moved relative to one another. The trigger forceadjustment mechanism 142 of FIG. 16A comprises one or more shims (e.g.,each shim providing about 100 grams of adjustment) placed between thespring 140 and at least one of the first portion and the second portion.The trigger force adjustment mechanism 142 of FIG. 16B comprises one,two, or more adjustment set screws. In either configuration, the triggerforce adjustment mechanism 142 compresses the spring 140 to adjust theamount of force which will move the first and second portions relativeto one another by a sufficient amount to trigger the apparatus 10. Incertain embodiments, the trigger force adjustment mechanism 142 is setsuch that the apparatus 10 is triggered by a pressure applied to theemission surface 22 towards the housing 12 of at least 0.1 pound persquare inch, at least one pound per square inch, or at least about twopounds per square inch.

In certain embodiments, the apparatus 10 further comprises a lensassembly sensor 150 configured to detect the presence of the outputoptical assembly 20 mounted on the apparatus 10. FIG. 17 schematicallyillustrates an example lens assembly sensor 150 in accordance withcertain embodiments described herein. For example, the lens assemblysensor 150 of certain embodiments comprises at least one reflectivesurface 152 and at least one light source/detector pair 154 a, 154 b(e.g., one, two, or more QRE1113GR reflective sensors available fromFairchild Semiconductor Corp. of San Jose, Calif.). The reflectivesurface 152 moves relative to the light source/detector pair 154 a, 154b upon mounting the output optical assembly 20 to be in thermalcommunication with the thermal conduit 92. For example, when the outputoptical assembly 20 is mounted, the bayonet is pulled downward. Inresponse to this movement, the sensor 150 generates a correspondingsignal. In certain embodiments, the sensor 150 further comprises ashroud 156 configured to protect the detector 154 b from stray light.

Control Circuit

FIG. 18 is a block diagram of a control circuit 200 comprising aprogrammable controller 205 for controlling a light source 207 accordingto embodiments described herein. The control circuit 200 is configuredto adjust the power of the light energy generated by the light source207 such that the light emitted from the emission surface 22 generates apredetermined surface irradiance at the scalp or skull corresponding toa predetermined energy delivery profile, such as a predeterminedsubsurface irradiance, to the target area of the brain.

In certain embodiments, the programmable controller 205 comprises alogic circuit 210, a clock 212 coupled to the logic circuit 210, and aninterface 214 coupled to the logic circuit 210. The clock 212 of certainembodiments provides a timing signal to the logic circuit 210 so thatthe logic circuit 210 can monitor and control timing intervals of theapplied light. Examples of timing intervals include, but are not limitedto, total treatment times, pulsewidth times for pulses of applied light,and time intervals between pulses of applied light. In certainembodiments, the light source 207 can be selectively turned on and offto reduce the thermal load on the scalp or skull and to deliver aselected irradiance to particular areas of the brain.

The interface 214 of certain embodiments provides signals to the logiccircuit 210 which the logic circuit 210 uses to control the appliedlight. The interface 214 can comprise a user interface or an interfaceto a sensor monitoring at least one parameter of the treatment. Incertain such embodiments, the programmable controller 126 is responsiveto signals from the sensor to preferably adjust the treatment parametersto optimize the measured response. The programmable controller 126 canthus provide closed-loop monitoring and adjustment of various treatmentparameters to optimize the phototherapy. The signals provided by theinterface 214 from a user are indicative of parameters that may include,but are not limited to, patient characteristics (e.g., skin type, fatpercentage), selected applied irradiances, target time intervals, andirradiance/timing profiles for the applied light.

In certain embodiments, the logic circuit 210 is coupled to a lightsource driver 220. The light source driver 220 is coupled to a powersupply 230, which in certain embodiments comprises a battery and inother embodiments comprises an alternating current source. The lightsource driver 220 is also coupled to the light source 207. The logiccircuit 210 is responsive to the signal from the clock 212 and to userinput from the user interface 214 to transmit a control signal to thelight source driver 220. In response to the control signal from thelogic circuit 210, the light source driver 220 adjust and controls thepower applied to the light source. Other control circuits besides thecontrol circuit 200 of FIG. 18 are compatible with embodiments describedherein.

In certain embodiments, the logic circuit 110 is responsive to signalsfrom a sensor monitoring at least one parameter of the treatment tocontrol the applied light. For example, certain embodiments comprise atemperature sensor in thermal communication with the scalp or skull toprovide information regarding the temperature of the scalp or skull tothe logic circuit 210. In such embodiments, the logic circuit 210 isresponsive to the information from the temperature sensor to transmit acontrol signal to the light source driver 220 so as to adjust theparameters of the applied light to maintain the scalp or skulltemperature below a predetermined level. Other embodiments includeexample biomedical sensors including, but not limited to, a blood flowsensor, a blood gas (e.g., oxygenation) sensor, an ATP productionsensor, or a cellular activity sensor. Such biomedical sensors canprovide real-time feedback information to the logic circuit 210. Incertain such embodiments, the logic circuit 110 is responsive to signalsfrom the sensors to preferably adjust the parameters of the appliedlight to optimize the measured response. The logic circuit 110 can thusprovide closed-loop monitoring and adjustment of various parameters ofthe applied light to optimize the phototherapy.

Light Parameters

The various parameters of the light beam emitted from the emissionsurface 22 are advantageously selected to provide treatment whilecontrolling, inhibiting, preventing, minimizing, or reducing injury ordiscomfort to the patient due to heating of the scalp or skull by thelight. While discussed separately, these various parameters below can becombined with one another within the disclosed values in accordance withembodiments described herein.

Wavelength

In certain embodiments, light in the visible to near-infrared wavelengthrange is used to irradiate the patient's scalp or skull. In certainembodiments, the light is substantially monochromatic (i.e., lighthaving one wavelength, or light having a narrow band of wavelengths). Sothat the amount of light transmitted to the brain is maximized, thewavelength of the light is selected in certain embodiments to be at ornear a transmission peak (or at or near an absorption minimum) for theintervening tissue. In certain such embodiments, the wavelengthcorresponds to a peak in the transmission spectrum of tissue at about820 nanometers. In certain other embodiments, the light comprises one ormore wavelengths between about 630 nanometers and about 1064 nanometers,between about 600 nanometers and about 980 nanometers, between about 780nanometers and about 840 nanometers, between about 805 nanometers andabout 820 nanometers, or includes wavelengths of about 785, 790, 795,800, 805, 810, 815, 820, 825, or 830 nanometers. An intermediatewavelength in a range between approximately 730 nanometers andapproximately 750 nanometers (e.g., about 739 nanometers) appears to besuitable for penetrating the skull, although other wavelengths are alsosuitable and may be used. In other embodiments, a plurality ofwavelengths is used (e.g. applied concurrently or sequentially). Incertain embodiments, the light has a wavelength distribution peaked at apeak wavelength and has a linewidth less than ±10 nanometers from thepeak wavelength. In certain such embodiments, the light has a linewidthless than 4 nanometers, full width at 90% of energy. In certainembodiments, the center wavelength is (808±10) nanometers with aspectral linewidth less than 4 nanometers, full width at 90% of energy.

In certain embodiments, the light is generated by a light sourcecomprising one or more laser diodes, which each provide coherent light.In embodiments in which the light from the light source is coherent, theemitted light may produce “speckling” due to coherent interference ofthe light. This speckling comprises intensity spikes which are createdby wavefront interference effects and can occur in proximity to thetarget tissue being treated. For example, while the average irradianceor power density may be approximately 10 mW/cm², the power density ofone such intensity spike in proximity to the brain tissue to be treatedmay be approximately 300 mW/cm². In certain embodiments, this increasedpower density due to speckling can improve the efficacy of treatmentsusing coherent light over those using incoherent light for illuminationof deeper tissues. In addition, the speckling can provide the increasedpower density without overheating the tissue being irradiated. The lightwithin the speckle fields or islands containing these intensity spikesis polarized, and in certain embodiments, this polarized light providesenhanced efficacy beyond that for unpolarized light of the sameintensity or irradiance.

In certain embodiments, the light source includes at least onecontinuously emitting GaAlAs laser diode having a wavelength of about830 nanometers. In another embodiment, the light source comprises alaser source having a wavelength of about 808 nanometers. In still otherembodiments, the light source includes at least one vertical cavitysurface-emitting laser (VCSEL) diode. Other light sources compatiblewith embodiments described herein include, but are not limited to,light-emitting diodes (LEDs) and filtered lamps.

In certain embodiments, the one or more wavelengths are selected so asto work with one or more chromophores within the target tissue. Withoutbeing bound by theory or by a specific mechanism, it is believed thatirradiation of chromophores increases the production of ATP in thetarget tissue and/or controls, inhibits, prevents, minimizes, or reducesapoptosis of the injured tissues, thereby producing beneficial effects,as described more fully below.

Some chromophores, such as water or hemoglobin, are ubiquitous andabsorb light to such a degree that little or no penetration of lightenergy into a tissue occurs. For example, water absorbs light aboveapproximately 1300 nanometers. Thus energy in this range has littleability to penetrate tissue due to the water content. However, water istransparent or nearly transparent in wavelengths between 300 and 1300nanometers. Another example is hemoglobin, which absorbs heavily in theregion between 300 and 670 nanometers, but is reasonably transparentabove 670 nanometers.

Based on these broad assumptions, one can define an “IR window” into thebody. Within the window, there are certain wavelengths that are more orless likely to penetrate. This discussion does not include wavelengthdependent scattering effects of intervening tissues.

The absorption/transmittance of various tissues have been directlymeasured to determine the utility of various wavelengths. FIG. 19A is agraph of the transmittance of light through blood (in arbitrary units)as a function of wavelength. Blood absorbs less in the region above 700nanometers, and is particularly transparent at wavelengths above 780nanometers. Wavelengths below 700 nanometers are heavily absorbed, andare not likely to be useful therapeutically (except for topicalindications).

FIG. 19B is a graph of the absorption of light by brain tissue.Absorption in the brain is strong for wavelengths between 620 and 980nanometers. This range is also where the copper centers in mitochondriaabsorb. The brain is particularly rich in mitochondria as it is a veryactive tissue metabolically (the brain accounts for 20% of blood flowand oxygen consumption). As such, the absorption of light in the 620 to980 nanometer range is expected if a photostimulative effect is to takeplace.

By combining FIGS. 19A and 19B, the efficiency of energy delivery as afunction of wavelength can be calculated, as shown in FIG. 19C.Wavelengths between 780 and 880 nanometers are preferable (efficiency of0.6 or greater) for targeting the brain. The peak efficiency is about800 to 830 nanometers (efficiency of 1.0 or greater). These wavelengthsare not absorbed by water or hemoglobin, and are likely to penetrate tothe brain. Once these wavelengths reach the brain, they will be absorbedby the brain and converted to useful energy.

These effects have been directly demonstrated in rat tissues. Theabsorption of 808 nanometer light was measured through various rattissues, as shown in FIG. 20. Soft tissues such as skin and fat absorblittle light. Muscle, richer in mitochondria, absorbs more light. Evenbone is fairly transparent. However, as noted above, brain tissue, aswell as spinal cord tissue, absorb 808 nanometer light well.

Irradiance or Power Density

In certain embodiments, the light beam has a time-averaged irradiance orpower density at the emission surface 22 of the output optical assembly20 between about 10 mW/cm² to about 10 W/cm², between about 100 mW/cm²to about 1000 mW/cm², between about 500 mW/cm² to about 1 W/cm², orbetween about 650 mW/cm² to about 750 mW/cm² across the cross-sectionalarea of the light beam. For a pulsed light beam, the time-averagedirradiance is averaged over a time period long compared to the temporalpulse widths of the pulses (e.g., averaged over a fraction of a secondlonger than the temporal pulse width, over 1 second, or over multipleseconds). For a continuous-wave (CW) light beam with time-varyingirradiance, the time-averaged irradiance can be an average of theinstantaneous irradiance averaged over a time period longer than acharacteristic time period of fluctuations of the light beam. In certainembodiments, a duty cycle in a range between 1% and 80%, between 10% and30%, or about 20% can be used with a peak irradiance at the emissionsurface 22 of the output optical assembly 20 between about 12.5 mW/cm²to about 1000 W/cm², between about 50 mW/cm² to about 50 W/cm², betweenabout 500 mW/cm² to about 5000 mW/cm², between about 2500 mW/cm² toabout 5 W/cm², or between about 3.25 W/cm² to about 3.75 W/cm² acrossthe cross-sectional area of the light beam. In certain embodiments, thepulsed light beam has an energy or fluence (e.g., peak irradiancemultiplied by the temporal pulsewidth) at the emission surface 22 of theoutput optical assembly 20 between about 12.5 μJ/cm² to about 1 J/cm²,between about 50 μJ/cm² to about 50 mJ/cm², between about 500 μJ/cm² toabout 5 mJ/cm², between about 2.5 mJ/cm² to about 5 mJ/cm², or betweenabout 3.25 mJ/cm² to about 3.75 mJ/cm².

The cross-sectional area of the light beam of certain embodiments (e.g.,multimode beams) can be approximated using an approximation of the beamintensity distribution. For example, as described more fully below,measurements of the beam intensity distribution can be approximated by aGaussian (1/e² measurements) or by a “top hat” distribution and aselected perimeter of the beam intensity distribution can be used todefine a bound of the area of the light beam. In certain embodiments,the irradiance at the emission surface 22 is selected to provide thedesired irradiances at the subdermal target tissue. The irradiance ofthe light beam is preferably controllably variable so that the emittedlight energy can be adjusted to provide a selected irradiance at thesubdermal tissue being treated. In certain embodiments, the light beamemitted from the emission surface 22 is continuous with a total radiantpower in a range of about 4 Watts to about 6 Watts. In certainembodiments, the radiant power of the light beam is 5 Watts±20% (CW). Incertain embodiments, the peak power for pulsed light is in a range ofabout 10 Watts to about 30 Watts (e.g., 20 Watts). In certainembodiments, the peak power for pulsed light multiplied by the dutycycle of the pulsed light yields an average radiant power in a range ofabout 4 Watts to about 6 Watts (e.g., 5 Watts).

In certain embodiments, the time-averaged irradiance at the subdermaltarget tissue (e.g., at a depth of approximately 2 centimeters below thedura) is at least about 0.01 mW/cm² and up to about 1 W/cm² at the levelof the tissue. In various embodiments, the time-averaged subsurfaceirradiance at the target tissue is at least about 0.01, 0.05, 0.1, 0.5,1, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, or 90 mW/cm², depending on thedesired clinical performance. In certain embodiments, the time-averagedsubsurface irradiance at the target tissue is about 0.01 mW/cm² to about100 mW/cm², about 0.01 mW/cm² to about 50 mW/cm², about 2 mW/cm² toabout 20 mW/cm², or about 5 mW/cm² to about 25 mW/cm². In certainembodiments, a duty cycle in a range between 1% and 80%, between 10% and30%, or about 20% can be used with a peak irradiance at the targettissue of 0.05 mW/cm² to about 500 mW/cm², about 0.05 mW/cm² to about250 mW/cm², about 10 mW/cm² to about 100 mW/cm², or about 25 mW/cm² toabout 125 mW/cm².

In certain embodiments, the irradiance of the light beam is selected toprovide a predetermined irradiance at the subdermal target tissue (e.g.,at a depth of approximately 2 centimeters from the dura). The selectionof the appropriate irradiance of the light beam emitted from theemission surface to use to achieve a desired subdermal irradiancepreferably includes consideration of scattering by intervening tissue.Further information regarding the scattering of light by tissue isprovided by U.S. Pat. No. 7,303,578, which is incorporated in itsentirety by reference herein, and V. Tuchin in “Tissue Optics: LightScattering Methods and Instruments for Medical Diagnosis,” SPIE Press(2000), Bellingham, Wash., pp. 3-11, which is incorporated in itsentirety by reference herein.

Phototherapy for the treatment of neurologic conditions (e.g., ischemicstroke, Alzheimer's Disease, Parkinson's Disease, depression, or TBI) isbased in part on the discovery that irradiance or power density (i.e.,power per unit area or number of photons per unit area per unit time)and energy density (i.e., energy per unit area or number of photons perunit area) of the light energy applied to tissue appear to besignificant factors in determining the relative efficacy of low levelphototherapy. This discovery is particularly applicable with respect totreating and saving surviving but endangered neurons in a zone of dangersurrounding the primary injury. Certain embodiments described herein arebased at least in part on the finding that, given a selected wavelengthof light energy, it is the irradiance and/or the energy density of thelight delivered to tissue (as opposed to the total power or total energydelivered to the tissue) that appears to be important factors indetermining the relative efficacy of phototherapy.

Without being bound by theory or by a specific mechanism, it is believedthat light energy delivered within a certain range of irradiances andenergy densities provides the desired biostimulative effect on theintracellular environment, such that proper function is returned topreviously nonfunctioning or poorly functioning mitochondria in at-riskneurons. The biostimulative effect may include interactions withchromophores within the target tissue, which facilitate production ofATP and/or controls, inhibits, prevents, minimizes, or reduces apoptosisof the injured cells which have experienced decreased blood flow (e.g.,due to the stroke or TBI). Because strokes and TBI correspond tointerruptions of blood flow to portions of the brain, it is thought thatany effects of increasing blood flow by phototherapy are of lessimportance in the efficacy of phototherapy for stroke or TBI victims.Further information regarding the role of irradiance and exposure timeis described by Hans H. F. I. van Breugel and P. R. Dop Bär in “PowerDensity and Exposure Time of He—Ne Laser Irradiation Are More ImportantThan Total Energy Dose in Photo-Biomodulation of Human Fibroblasts InVitro,” Lasers in Surgery and Medicine, Volume 12, pp. 528-537 (1992),which is incorporated in its entirety by reference herein. In addition,the significance of the irradiance used in phototherapy with regard tothe devices and methods used in phototherapy of brain tissue, aredescribed more fully in U.S. Pat. No. 7,303,578 and in U.S. Patent Appl.Publ. Nos. 2005/0107851 A1, 2007/0179570 A1, and 2007/0179571 A1, eachof which is incorporated in its entirety by reference herein. Whilethese previous discussions of irradiance were primarily in conjunctionwith phototherapy of stroke, they apply as well to phototherapy of TBI.For example, in certain embodiments, to obtain a desired average powerdensity at the brain for treating TBI, higher total power at the scalpor skull can be used in conjunction with a larger spot size at the scalpor skull. Thus, by increasing the spot size at the scalp or skull, adesired average power density at the brain can be achieved with lowerpower densities at the scalp or skull which can reduce the possibilityof overheating the scalp, skull, or brain.

In certain embodiments, delivering the neuroprotective amount of lightenergy includes selecting a surface irradiance of the light energy atthe scalp or skull corresponding to the predetermined irradiance at thetarget area of the brain. As described above, light propagating throughtissue is scattered and absorbed by the tissue. Calculations of theirradiance to be applied to the scalp or skull so as to deliver apredetermined irradiance to the selected target area of the brainpreferably take into account the attenuation of the light energy as itpropagates through the skin and other tissues, such as bone and braintissue. Factors known to affect the attenuation of light propagating tothe brain from the scalp or skull include, but are not limited to, skinpigmentation, the presence, type, and color of hair over the area to betreated, amount of fat tissue, the presence of bruised tissue, skullthickness, patient's age and gender, and the location of the target areaof the brain, particularly the depth of the area relative to the surfaceof the scalp or skull. (For a general discussion of the absorption oflight by melanins in the body, see, e.g., “Optical Absorption Spectra ofMelanins—a Comparison of Theoretical and Experimental Results,”accelrys.com/references/case-studies/melanins_partII.pdf) The higher thelevel of skin pigmentation, the higher the irradiance applied to thescalp to deliver a predetermined irradiance of light energy to asubsurface site of the brain. The target area of the patient's brain canbe previously identified such as by using standard medical imagingtechniques.

The irradiance selected to be applied to the target area of thepatient's brain depends on a number of factors, including, but notlimited to, the wavelength of the applied light, the type of CVA(ischemic or hemorrhagic), and the patient's clinical condition,including the extent of the affected brain area. The irradiance or powerdensity of light energy to be delivered to the target area of thepatient's brain may also be adjusted to be combined with any othertherapeutic agent or agents, especially pharmaceutical neuroprotectiveagents, to achieve the desired biological effect. In such embodiments,the selected irradiance can also depend on the additional therapeuticagent or agents chosen.

Temporal Pulsewidth, Temporal Pulseshape, Duty Cycle, Repetition Rate,and Irradiance per Pulse

FIG. 21A schematically illustrates a generalized temporal profile of apulsed light beam in accordance with certain embodiments describedherein. The temporal profile comprises a plurality of pulses (P₁, P₂, .. . , P_(i)), each pulse having a temporal pulsewidth during which theinstantaneous intensity or irradiance I(t) of the pulse is substantiallynon-zero. For example, for the pulsed light beam of FIG. 21A, pulseP_(i) has a temporal pulsewidth from time t=0 to time t=T_(i), pulse P₂has a temporal pulsewidth from time t=T₂ to time t=T₃, and pulse P_(i)has a temporal pulsewidth from time t=T_(i) to time t=T_(i+). Thetemporal pulsewidth can also be referred to as the “pulse ON time.” Thepulses are temporally spaced from one another by periods of time duringwhich the intensity or irradiance of the beam is substantially zero. Forexample, pulse P₁ is spaced in time from pulse P₂ by a time t=T₂−T₁. Thetime between pulses can also be referred to as the “pulse OFF time.” Incertain embodiments, the pulse ON times of the pulses are substantiallyequal to one another, while in certain other embodiments, the pulse ONtimes differ from one another. In certain embodiments, the pulse OFFtimes between the pulses are substantially equal to one another, whilein certain other embodiments, the pulse OFF times between the pulsesdiffer from one another. As used herein, the term “duty cycle” has itsbroadest reasonable interpretation, including but not limited to, thepulse ON time divided by the sum of the pulse ON time and the pulse OFFtime. For a pulsed light beam, the duty cycle is less than one. Thevalues of the duty cycle and the temporal pulsewidth fully define therepetition rate of the pulsed light beam.

Each of the pulses can have a temporal pulseshape which describes theinstantaneous intensity or irradiance of the pulse I(t) as a function oftime. For example, as shown in FIG. 21A, the temporal pulseshapes of thepulsed light beam are irregular, and are not the same among the variouspulses. In certain embodiments, the temporal pulseshapes of the pulsedlight beam are substantially the same among the various pulses. Forexample, as schematically shown in FIG. 21B, the pulses can have asquare temporal pulseshape, with each pulse having a substantiallyconstant instantaneous irradiance over the pulse ON time. In certainembodiments, the peak irradiances of the pulses differ from one another(see, e.g., FIGS. 21A and 21B), while in certain other embodiments, thepeak irradiances of the pulses are substantially equal to one another(see, e.g., FIGS. 21C and 21D). Various other temporal pulseshapes(e.g., triangular, trapezoidal) are also compatible with certainembodiments described herein. FIG. 21C schematically illustrates aplurality of trapezoidal pulses in which each pulse has a rise time(e.g., corresponding to the time between an instantaneous irradiance ofzero and a peak irradiance of the pulse) and a fall time (e.g.,corresponding to the time between the peak irradiance of the pulse andan instantaneous irradiance of zero). In certain embodiments, the risetime and the fall time can be expressed relative to a specified fractionof the peak irradiance of the pulse (e.g., time to rise/fall to 50% ofthe peak irradiance of the pulse).

As used herein, the term “peak irradiance” of a pulse P_(i) has itsbroadest reasonable interpretation, including but not limited to, themaximum value of the instantaneous irradiance I(t) during the temporalpulsewidth of the pulse. In certain embodiments, the instantaneousirradiance is changing during the temporal pulsewidth of the pulse (see,e.g., FIGS. 21A and 21C), while in certain other embodiments, theinstantaneous irradiance is substantially constant during the temporalpulsewidth of the pulse (see, e.g., FIGS. 21B and 21D).

As used herein, the term “pulse irradiance” I_(P) _(i) of a pulse P_(i)has its broadest reasonable interpretation, including but not limitedto, the integral of the instantaneous irradiance I(t) of the pulse P_(i)over the temporal pulsewidth of the pulse:

I_(P_(i)) = ∫_(T_(i))^(T_(i + 1))I(t) ⋅ d t/(T_(i + 1) − T_(i)).As used herein, the term “total irradiance” I_(TOTAL) has its broadestreasonable interpretation, including but not limited to, the sum of thepulse irradiances of the pulses:

$I_{TOTAL} = {\sum\limits_{i = 0}^{N}{I_{P_{i}}.}}$As used herein, the term “time-averaged irradiance” I_(AVE) has itsbroadest reasonable interpretation, including but not limited to, theintegral of the instantaneous irradiance I(t) over a period of time Tlarge compared to the temporal pulsewidths of the pulses:

I_(AVE) = ∫₀^(T)I(t) ⋅ d t/T.The integral

∫₀^(T)I(t) ⋅ d tprovides the energy of the pulsed light beam.

For example, for a plurality of square pulses with different pulseirradiances I_(P) _(i) and different temporal pulsewidths αT_(i), thetime-averaged irradiance over a time T equals

$I_{AVE} = {\frac{1}{T}{\sum\limits_{i}{{I_{P_{i}} \cdot \Delta}\;{T_{i}.}}}}$For another example, for a plurality of square pulses with equal pulseirradiances I_(P), with equal temporal pulsewidths, and equal pulse OFFtimes (having a duty cycle D), the time-averaged irradiance equalsI_(AVE)=I_(P)·D. For example, as shown in FIG. 21D, the time-averagedirradiance (shown as a dashed line) is less than the pulse irradiance ofthe pulses.

The pulse irradiances and the duty cycle can be selected to provide apredetermined time-averaged irradiance. In certain embodiments in whichthe time-averaged irradiance is equal to the irradiance of acontinuous-wave (CW) light beam, the pulsed light beam and the CW lightbeam have the same number of photons or flux as one another. Forexample, a pulsed light beam with a pulse irradiance of 5 mW/cm² and aduty cycle of 20% provides the same number of photons as a CW light beamhaving an irradiance of 1 mW/cm². However, in contrast to a CW lightbeam, the parameters of the pulsed light beam can be selected to deliverthe photons in a manner which achieve results which are not obtainableusing CW light beams.

For example, for hair removal, tattoo removal, or wrinkle smoothing,pulsed light beams have previously been used to achieve selectivephotothermolysis in which a selected portion of the skin is exposed tosufficiently high temperatures to damage the hair follicles (e.g.,temperatures greater than 60 degrees Celsius), to ablate the tattoo ink(e.g., temperatures much greater than 60 degrees Celsius), or to shrinkthe collagen molecules (e.g., temperatures between 60-70 degreesCelsius), respectively, while keeping the other portions of skin atsufficiently low temperatures to avoid unwanted damage or discomfort.The parameters of these pulsed light beams are selected to achieve thedesired elevated temperature at the selected portion of the skin byabsorption of the light by the selected chromophore while allowing heatto dissipate (characterized by a thermal relaxation time) during thepulse OFF times to keep other areas of skin at lower temperatures. Asdescribed by J. Lepselter et al., “Biological and clinical aspects inlaser hair removal,” J. Dermatological Treatment, Vol. 15, pp. 72-83(2004), the pulse ON time for hair removal is selected to be between thethermal relaxation time for the epidermis (about 3-10 milliseconds) andthe thermal relaxation time for the hair follicle (about 40-100milliseconds). In this way, the hair follicle can be heated tosufficiently high temperatures to damage the follicle without causingexcessive damage to the surrounding skin.

In contrast to these treatments which are based on creating thermaldamage to at least a portion of the skin, certain embodiments describedherein utilize pulse parameters which do not create thermal damage to atleast a portion of the skin. In certain embodiments, one or more of thetemporal pulsewidth, temporal pulseshape, duty cycle, repetition rate,and pulse irradiance of the pulsed light beam are selected such that noportion of the skin is heated to a temperature greater than 60 degreesCelsius, greater than 55 degrees Celsius, greater than 50 degreesCelsius, or greater than 45 degrees Celsius. In certain embodiments, oneor more of the temporal pulsewidth, temporal pulseshape, duty cycle,repetition rate, and pulse irradiance of the pulsed light beam areselected such that no portion of the skin is heated to a temperaturegreater than 30 degrees Celsius above its baseline temperature, greaterthan 20 degrees Celsius above its baseline temperature, or greater than10 degrees Celsius above its baseline temperature. In certainembodiments, one or more of the temporal pulsewidth, temporalpulseshape, duty cycle, repetition rate, and pulse irradiance of thepulsed light beam are selected such that no portion of the brain isheated to a temperature greater than 5 degrees Celsius above itsbaseline temperature, greater than 3 degrees Celsius above its baselinetemperature, or greater than 1 degree Celsius above its baselinetemperature. As used herein, the term “baseline temperature” has itsbroadest reasonable interpretation, including but not limited to, thetemperature at which the tissue would have if it were not irradiated bythe light. In contrast to previous low-light level therapies, the pulsedlight beam has an average radiant power in the range of about 1 Watt toabout 6 Watts or in a range of about 4 Watt to about 6 Watts.

In certain embodiments, the pulse parameters are selected to achieveother effects beyond those which are achievable using CW light beams.For example, while CW irradiation of brain cells in vivo provides anefficacious treatment of stroke, the use of CW irradiation for thetreatment of TBI is more difficult, owing in part to the excess bloodwithin the region of the scalp, skull, or cranium to be irradiated(e.g., due to intercranial bleeding). This excess blood may be betweenthe light source and the target brain tissue to be irradiated, resultingin higher absorption of the light applied to the scalp or skull beforeit can propagate to the target tissue. This absorption can reduce theamount of light reaching the target tissue and can unduly heat theintervening tissue to an undesirable level.

In certain embodiments described herein, pulsed irradiation may providea more efficacious treatment. The pulsed irradiation can provide higherpeak irradiances for shorter times, thereby providing more power topropagate to the target tissue while allowing thermal relaxation of theintervening tissue and blood between pulses to avoid unduly heating theintervening tissue. The time scale for the thermal relaxation istypically in the range of a few milliseconds. For example, the thermalrelaxation time constant (e.g., the time for tissue to cool from anelevated temperature to one-half the elevated temperature) of human skinis about 3-10 milliseconds, while the thermal relaxation time constantof human hair follicles is about 40-100 milliseconds. Thus, previousapplications of pulsed light to the body for hair removal have optimizedtemporal pulsewidths of greater than 40 milliseconds with time betweenpulses of hundreds of milliseconds.

However, while pulsed light of this time scale advantageously reducesthe heating of intervening tissue and blood, it does not provide anoptimum amount of efficaciousness as compared to other time scales. Incertain embodiments described herein, the patient's scalp or skull isirradiated with pulsed light having parameters which are not optimizedto reduce thermal effects, but instead are optimized to stimulate, toexcite, to induce, or to otherwise support one or more intercellular orintracellular biological processes which are involved in the survival,regeneration, or restoration of performance or viability of brain cells.Thus, in certain such embodiments, the selected temporal profile canresult in temperatures of the irradiated tissue which are higher thanthose resulting from other temporal profiles, but which are moreefficacious than these other temporal profiles. In certain embodiments,the pulsing parameters are selected to utilize the kinetics of thebiological processes rather than optimizing the thermal relaxation ofthe tissue. In certain embodiments, the pulsed light beam has a temporalprofile (e.g., peak irradiance per pulse, a temporal pulse width, and apulse duty cycle) selected to modulate membrane potentials in order toenhance, restore, or promote cell survival, cell function, or both ofthe irradiated brain cells following the traumatic brain injury. Forexample, in certain embodiments, the pulsed light has a temporal profilewhich supports one or more intercellular or intracellular biologicalprocesses involved in the survival or regeneration of brain cells, butdoes not optimize the thermal relaxation of the irradiated tissue. Incertain embodiments, the brain cells survive longer after theirradiation as compared to their survival if the irradiation did notoccur. For example, the light of certain embodiments can have aprotective effect on the brain cells, or can cause a regenerationprocess in the brain cells.

In certain embodiments, the temporal profile (e.g., peak irradiance,temporal pulse width, and duty cycle) are selected to utilize thekinetics of the biological processes while maintaining the irradiatedportion of the scalp or skull at or below a predetermined temperature.This predetermined temperature is higher than the optimized temperaturewhich could be achieved for other temporal profiles (e.g., other valuesof the peak irradiance, temporal pulse width, and duty cycle) which areoptimized to minimize the temperature increase of surrounding tissue dueto the irradiation. For example, a temporal profile having a peakirradiance of 10 W/cm² and a duty cycle of 20% has a time-averagedirradiance of 2 W/cm². Such a pulsed light beam provides the same numberof photons to the irradiated surface as does a continuous-wave (CW)light beam with an irradiance of 2 W/cm². However, because of the “darktime” between pulses, the pulsed light beam can result in a lowertemperature increase than does the CW light beam. To minimize thetemperature increase of the irradiated portion of the scalp or skull,the temporal pulse width and the duty cycle can be selected to allow asignificant portion of the heat generated per pulse to dissipate beforethe next pulse reaches the irradiated portion. In certain embodimentsdescribed herein, rather than optimizing the beam temporal parameters tominimize the temperature increase, the temporal parameters are selectedto effectively correspond to or to be sufficiently close to the timingof the biomolecular processes involved in the absorption of the photonsto provide an increased efficacy. Rather than having a temporal pulsewidth on the order of hundreds of microseconds, certain embodimentsdescribed herein utilize a temporal pulse width which does not optimizethe thermal relaxation of the irradiated tissue (e.g., milliseconds,tens of milliseconds, hundreds of milliseconds). Since these pulsewidths are significantly longer than the thermal relaxation time scale,the resulting temperature increases are larger than those of smallerpulse widths, but still less than that of CW light beams due to the heatdissipation the time between the pulses.

A number of studies have investigated the effects of in vitroirradiation of cells using pulsed light on various aspects of the cells.A study of the action mechanisms of incoherent pulsed radiation at awavelength of 820 nanometers (pulse repetition frequency of 10 Hz, pulsewidth of 20 milliseconds, dark period between pulses of 80 milliseconds,and duty factor (pulse duration to pulse period ratio) of 20%) on invitro cellular adhesion has found that pulsed infrared radiation at 820nanometers increases the cell-matrix attachment. (T. I. Karu et al.,“Cell Attachment to Extracellular Matrices is Modulated by PulsedRadiation at 820 nm and Chemicals that Modify the Activity of Enzymes inthe Plasma Membrane,” Lasers in Surgery and Medicine, Vol. 29, pp.274-281 (2001) which is incorporated in its entirety by referenceherein.) It was hypothesized in this study that the modulation of themonovalent ion fluxes through the plasma membrane, and not the releaseof arachidonic acid, is involved in the cellular signaling pathwaysactivated by irradiation at 820 nanometers. A study of light-inducedchanges to the membrane conductance of ventral photoreceptor cells foundbehavior which was dependent on the pulse parameters, indicative of twolight-induced membrane processes. (J. E. Lisman et al., “TwoLight-Induced Processes in the Photoreceptor Cells of Limulus VentralEye,” J. Gen. Physiology, Vol. 58, pp. 544-561 (1971), which isincorporated in its entirety by reference herein.) Studies oflaser-activated electron injection into oxidized cytochrome c oxidaseobserved kinetics which establish the reaction sequence of the protonpump mechanism and some of its thermodynamic properties have timeconstants on the order of a few milliseconds. (I. Belevich et al.,“Exploring the proton pump mechanism of cytochrome c oxidase in realtime,” Proc. Nat'l Acad. Sci., Vol. 104, pp. 2685-2690 (2007); I.Belevich et al., “Proton-coupled electron transfer drives the protonpump of cytochrome c oxidase,” Nature, Vol. 440, pp. 829-832 (2006),both of which are incorporated in its entirety by reference herein.) Anin vivo study of neural activation based on pulsed infrared lightproposed a photo-thermal effect from transient tissue temperaturechanges resulting in direct or indirect activation of transmembrane ionchannels causing propagation of the action potential. (J. Wells et al.,“Biophysical mechanisms responsible for pulsed low-level laserexcitation of neural tissue,” Proc. SPIE, Vol. 6084, pp. 60840X (2006),which is incorporated in its entirety by reference herein.)

In certain embodiments, the temporal profile of the pulsed light beamcomprises a peak irradiance, a temporal pulse width, a temporal pulseshape, a duty cycle, and a pulse repetition rate or frequency. Incertain embodiments in which the pulsed light beam is transmittedthrough a region of the scalp or skull containing an excess amount ofhemorrhagic blood due to the at least one physical trauma (e.g., due tointercranial bleeding), at least one of the peak irradiance, temporalpulse width, temporal pulse shape, duty cycle, and pulse repetition rateor frequency is selected to provide a time-averaged irradiance (averagedover a time period including a plurality of pulses) at the emissionsurface 22 of the output optical assembly 20 between about 10 mW/cm² toabout 10 W/cm², between about 100 mW/cm² to about 1000 mW/cm², betweenabout 500 mW/cm² to about 1 W/cm², or between about 650 mW/cm² to about750 mW/cm² across the cross-sectional area of the light beam. In certainsuch embodiments, the time-averaged irradiance at the brain cells beingtreated (e.g., at a depth of approximately 2 centimeters below the dura)is greater than 0.01 mW/cm².

In certain embodiments, the peak irradiance per pulse across thecross-sectional area of the light beam at the emission surface 22 of theoutput optical assembly 20 is in a range between about 10 mW/cm² toabout 10 W/cm², between about 100 mW/cm² to about 1000 mW/cm², betweenabout 500 mW/cm² to about 1 W/cm², between about 650 mW/cm² to about 750mW/cm², between about 20 mW/cm² to about 20 W/cm², between about 200mW/cm² to about 2000 mW/cm², between about 1 W/cm² to about 2 W/cm²,between about 1300 mW/cm² to about 1500 mW/cm², between about 1 W/cm² toabout 1000 W/cm², between about 10 W/cm² to about 100 W/cm², betweenabout 50 W/cm² to about 100 W/cm², or between about 65 W/cm² to about 75W/cm². In certain embodiments, the temporal pulse shape is generallyrectangular, generally triangular, or any other shape. In certainembodiments, the pulses have a rise time (e.g., from 10% of the peakirradiance to 90% of the peak irradiance) less than 1% of the pulse ONtime, or a fall time (e.g., from 90% of the peak irradiance to 10% ofthe peak irradiance) less than 1% of the pulse ON time.

In certain embodiments, the pulses have a temporal pulsewidth (e.g.,pulse ON time) in a range between about 0.001 millisecond and about 150seconds, between about 0.01 millisecond and about 10 seconds, betweenabout 0.1 millisecond and about 1 second, between about 0.5 millisecondand about 100 milliseconds, between about 2 milliseconds and about 20milliseconds, or between about 1 millisecond and about 10 milliseconds.In certain embodiments, the pulse width is about 0.5, 1, 2, 4, 6, 8, 10,15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220,240, 260, 280, or 300 milliseconds. In certain embodiments, the temporalpulsewidth is in a range between about 0.1 millisecond and 150 seconds.

In certain embodiments, the time between pulses (e.g., pulse OFF time)is in a range between about 0.01 millisecond and about 150 seconds,between about 0.1 millisecond and about 100 millisecond, between about 4milliseconds and about 1 second, between about 8 milliseconds and about500 milliseconds, between about 8 milliseconds and about 80milliseconds, or between about 10 milliseconds and about 200milliseconds. In certain embodiments, the time between pulses is about4, 8, 10, 20, 50, 100, 200, 500, 700, or 1000 milliseconds.

In certain embodiments, the pulse duty cycle is in a range between about1% and about 80% or in a range between about 10% and about 30%. Incertain embodiments, the pulse duty cycle is about 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, or 90%.

Beam Size and Beam Profile

In certain embodiments, the light beam emitted from the output opticalassembly 20 has a nominal diameter in a range of about 10 millimeters toabout 40 millimeters, in a range of about 20 millimeters to about 35millimeters, or equal to about 30 millimeters. In certain embodiments,the cross-sectional area is generally circular with a radius in a rangeof about 1 centimeter to about 2 centimeters. In certain embodiments,the light beam emitted from the emission surface 22 has across-sectional area greater than about 2 cm² or in a range of about 2cm² to about 20 cm² at the emission surface 22 of the optical element23. In certain embodiments, the output optical element 23 has anaperture diameter of less than 33 millimeters.

As used herein, the beam diameter is defined to be the largest chord ofthe perimeter of the area of the scalp or skull irradiated by the lightbeam at an intensity of at least 1/e² of the maximum intensity of thelight beam. The perimeter of the light beam used to determine thediameter of the beam is defined in certain embodiments to be thosepoints at which the intensity of the light beam is 1/e² of the maximumintensity of the light beam. The maximum-useful diameter of certainembodiments is limited by the size of the patient's head and by theheating of the patient's head by the irradiation. The minimum-usefuldiameter of certain embodiments is limited by heating and by the totalnumber of treatment sites that could be practically implemented. Forexample, to cover the patient's skull with a beam having a small beamdiameter would correspondingly use a large number of treatment sites. Incertain embodiments, the time of irradiation per treatment site can beadjusted accordingly to achieve a desired exposure dose.

Specifying the total flux inside a circular aperture with a specifiedradius centered on the exit aperture (“encircled energy”) is a method ofspecifying the power (irradiance) distribution over the light beamemitted from the emission surface 22. The “encircled energy” can be usedto ensure that the light beam is not too concentrated, too large, or toosmall. In certain embodiments, the light beam emitted from the emissionsurface has a total radiant power, and the light beam has a total fluxinside a 20-millimeter diameter cross-sectional circle centered on thelight beam at the emission surface 22 which is no more than 75% of thetotal radiant power. In certain such embodiments, the light beam has atotal flux inside a 26-millimeter diameter cross-sectional circlecentered on the light beam at the emission surface 22 which is no lessthan 50% of the total radiant power.

In certain embodiments, the beam intensity profile has a semi-Gaussianprofile, while in certain other embodiments, the beam intensity profilehas a “top hat” profile. In certain embodiments, the light beam issubstantially without high flux regions or “hot spots” in the beamintensity profile in which the local flux, averaged over a 3 millimeterby 3 millimeter area, is more than 10% larger than the average flux.Certain embodiments of the apparatus 10 advantageously generate a lightbeam substantially without hot spots, thereby avoiding large temperaturegradients at the patient's skin which would otherwise cause discomfortto the patient.

Divergence

In certain embodiments, the beam divergence emitted from the emissionsurface 22 is significantly less than the scattering angle of lightinside the body tissue being irradiated, which is typically severaldegrees. In certain embodiments, the light beam has a divergence anglegreater than zero and less than 35 degrees.

As the distance between a light source and an observer increases, thediameter of the source becomes less relevant to considerations of thebeam divergence. For example, an end of the optical fiber 40 providingthe light has a diameter of about 1 millimeter. At a close distance,observing from a specific location, light rays from the edges of theoptical fiber end can arrive at the observation point with significantlydifferent angles. However, as the observation point moves away from thelight source, this angular discrepancy is reduced and the source appearsmore like a point source.

In certain embodiments, with the output optical assembly 20 mounted ontothe apparatus 10, the optical distance between the emission surface 22and the end of the optical fiber 40 is about 82.7 millimeters. The beamdivergence dictated by the numerical aperture of the optical fiber 40and the exit aperture of the optical element 23 is about 23 degrees. Incertain embodiments, with the output optical assembly 20 not mountedonto the apparatus 10, the optical distance between the window 70 andthe end of the optical fiber is about 57.5 millimeters, and the beamdivergence dictated by the numerical aperture of the optical fiber 40and the exit aperture of the window 70 is about 16 degrees. With asource diameter of about 1 millimeter, the angular ambiguity in the beamdivergence is about ±0.35 degree. Thus, the angular ambiguity is muchless than the beam divergence angle regardless of whether the outputoptical assembly 20 is mounted or not onto the apparatus 10, so theoptical fiber 40 can be treated as a point source. In certain suchembodiments, the beam divergence or radiant intensity (e.g., measured inWatts/steradian) can be calculated directly from the beam profile orfrom the irradiance.

Treatment Time

In certain embodiments, the treatment per treatment site proceedscontinuously for a period of about 10 seconds to about 2 hours, for aperiod of about 1 to about 10 minutes, or for a period of about 1 to 5minutes. For example, the treatment time per treatment site in certainembodiments is about two minutes. In other embodiments, the light energyis delivered for at least one treatment period of at least about fiveminutes, or for at least one treatment period of at least ten minutes.The minimum treatment time of certain embodiments is limited by thebiological response time (which is on the order of microseconds). Themaximum treatment time of certain embodiments is limited by heating andby practical treatment times (e.g., completing treatment within about 24hours of stroke onset). The light energy can be pulsed during thetreatment period or the light energy can be continuously applied duringthe treatment period. If the light is pulsed, the pulses can be 2milliseconds long and occur at a frequency of 100 Hz, although longerpulselengths and lower frequencies can be used, or at least about 10nanosecond long and occur at a frequency of up to about 100 kHz.

In certain embodiments, the treatment may be terminated after onetreatment period, while in other embodiments, the treatment may berepeated for at least two treatment periods. The time between subsequenttreatment periods can be at least about five minutes, at least two in a24-hour period, at least about 1 to 2 days, or at least about one week.The length of treatment time and frequency of treatment periods candepend on several factors, including the functional recovery of thepatient and the results of imaging analysis of the injury (e.g.,infarct). In certain embodiments, one or more treatment parameters canbe adjusted in response to a feedback signal from a device (e.g.,magnetic resonance imaging) monitoring the patient.

Cooling Parameters

In certain embodiments, the apparatus 10 comprises an output opticalelement 23 in optical communication with a source of light. The outputoptical element 23 comprises an emission surface 22 configured to emit alight beam in accordance with the light parameters disclosed above. Incertain embodiments the apparatus 10 further comprises a thermallyconductive portion configured to be placed in thermal communication withthe irradiated portion of the patient's scalp or skull and to removeheat from the irradiated portion of the patient's scalp or skull. Incertain embodiments, the thermally conductive portion comprises theoutput optical element 23. The thermally conductive portion of certainembodiments is releasably coupled to the output optical element 23.

In certain embodiments, the thermally conductive portion removes heatfrom the irradiated portion of the patient's scalp or skull. Thiscooling of the scalp or skull can to improve the comfort of the patient,by controlling, inhibiting, preventing, minimizing, or reducingtemperature increases at the scalp or skull due to the irradiation.Thus, by virtue of the cooling of the portion of the patient's scalp orskull being irradiated, the temperature of the irradiated portion of thepatient's scalp or skull is lower than it would otherwise be if theirradiated portion of the scalp or skull were not cooled. For example,by cooling the irradiated portion of the patient's scalp or skull, thetemperature of the irradiated portion of the patient's scalp or skullcan be higher than the temperature of the portion of the patient's scalpor skull if it were not irradiated, but lower than the temperature ofthe portion of the patient's scalp or skull if it were irradiated butnot cooled. In addition, this cooling of the scalp or skull can be toperform double-blind studies of the efficacy of the phototherapytreatment by masking any heating of the scalp or skull due to theirradiation. (See, e.g., B. Catanzaro et al., “Managing Tissue Heatingin Laser Therapy to Enable Double-Blind Clinical Study,” Mechanisms forLow-Light Therapy, Proc. of the SPIE, Vol. 6140, pp. 199-208 (2006).)

In certain embodiments, heat is removed from the irradiated portion ofthe patient's scalp or skull by the thermally conductive portion at arate in a range of about 0.1 Watt to about 5 Watts or in a range ofabout 1 Watt to about 3 Watts. In certain embodiments, the thermallyconductive portion is configured to maintain the temperature of theirradiated portion of the patient's scalp or skull to be less than 42degrees Celsius. The thermally conductive portion of certain embodimentsis in thermal communication with the emission surface 22 and isconfigured to maintain the temperature of the emission surface to be ina range of 18 degrees Celsius to 25 degrees Celsius under a heat load of2 Watts. For a general description of cooling of the scalp, see, e.g.,F. E. M. Janssen et al., “Modeling of temperature and perfusion duringscalp cooling,” Phys. Med. Biol., Vol. 50, pp. 4065-4073 (2005). Incertain embodiments in which pulsed light is used, the rate of heatremoval can be less, or cooling may not be utilized for certain rangesof pulsed dosimetries and timing.

Pressure Parameters

In certain embodiments, the apparatus 10 is configured to have thethermally conductive portion move relative to a second portion of theapparatus 10 upon a pressure being applied to the thermally conductiveportion above a predetermined threshold pressure in a direction ofmovement of the thermally conductive portion relative to the secondportion of the apparatus 10. The predetermined threshold pressure issufficient to have the thermally conductive portion in thermalcommunication with the portion of the patient's scalp or skull. Incertain such embodiments, the apparatus 10 comprises a sensor configuredto be responsive to the movement of the thermally conductive portionrelative to the second portion by generating a signal (e.g., binary,analog, or digital) indicative of the movement.

In certain such embodiments, the sensor 130 in conjunction with thetrigger force spring 140 and the trigger force adjustment mechanism 142provides a mechanism for detecting whether the apparatus 10 is beingapplied to the patient's scalp or skull with a pressure above thepredetermined threshold pressure. In certain such embodiments, thesensor 130 detects movement between the first portion of the apparatus10 and the second portion of the apparatus 10 upon placing the emissionsurface 22 in thermal communication with the patient's scalp or skullwith sufficient pressure to overcome the restoring force of the triggerforce spring 140. Upon applying the threshold pressure to the emissionsurface 22 move the first and second portions relative to one another,the sensor 130 detects the movement and generates a correspondingsignal. In certain embodiments, the apparatus 10 further comprises acontroller operatively coupled to the light source and to the sensor130. The controller is configured to receive the signal from the sensor130 and to turn on the light source in response to the signal beingindicative of the pressure being above the predetermined thresholdpressure.

In certain embodiments, the threshold pressure is set to be a pressurewhich results in blanching of the portion of the patient's scalp to beirradiated. In certain embodiments, the threshold pressure is 0.1 poundper square inch, while in certain other embodiments, the thresholdpressure is one pound per square inch or about two pounds per squareinch.

In certain embodiments in which pulsed light is used, the amount ofblanching can be less, or blanching may not be utilized for certainranges of pulsed dosimetries and timing. For example, in certainembodiments, the patient may have a heightened sensitivity to pressureapplied to the scalp or skull (e.g., a TBI patient). Thus, in certainembodiments, the apparatus 10 does not apply sufficient pressure to thescalp of the patient (e.g., applies no pressure to the patient's scalp)to blanch the irradiated portion of the scalp during the irradiation. Incertain other embodiments in which some amount of blanching of theirradiated portion of the scalp is desired, the maximum pressure used toblanch the irradiated portion of the scalp is limited by patient comfortlevels and tissue damage levels. For example, the cranium or skull of aTBI patient may have cracks or breaks such that the brain would beadversely affected if pressure were applied to the scalp. The amount ofpressure used, if any, is determined at least in part, on the amount ofpressure that the patient can withstand without additional damage beingdone by the application of pressure.

Irradiating Multiple Portions of the Scalp or Skull

FIGS. 22A-22C schematically illustrate an embodiment in which theapparatus 10 is placed in thermal communication sequentially with aplurality of treatment sites corresponding to portions of the patient'sscalp. In certain such embodiments, the light emitted from the emissionsurface 22 propagates through the scalp to the brain and disperses in adirection generally parallel to the scalp, as shown in FIG. 22A. Incertain embodiments in which the patient is suffering from a TBI, one ormore of the treatment sites has a portion of the skull exposed and atleast a portion of the light is applied to the exposed portion of theskull without propagating through scalp tissue. In certain embodiments,the treatment sites of the patient's scalp do not overlap one another.The treatment sites (e.g., twenty treatment sites) are preferably spacedsufficiently far apart from one another such that the light emitted fromthe emission surface 22 to irradiate a treatment site of the patient'sscalp is transmitted through intervening tissue to irradiate an area ofthe patient's brain which overlaps one or more areas of the targettissue of the patient's brain irradiated by the light emitted from theemission surface 22 when a neighboring treatment site of the patient'sscalp is irradiated. FIG. 22B schematically illustrates this overlap asthe overlap of circular spots 160 across the target tissue at areference depth at or below the surface of the brain. FIG. 22Cschematically illustrates this overlap as a graph of the irradiance atthe reference depth of the brain along the line L-L of FIGS. 22A and22B. Summing the irradiances from the neighboring treatment sites (shownas a dashed line in FIG. 22C) serves to provide a more uniform lightdistribution at the target tissue to be treated. In such embodiments,the summed irradiance is preferably less than a damage threshold of thebrain and above an efficacy threshold. In certain embodiments, portionsof the brain irradiated by irradiating the treatment sites at the scalpdo not overlap one another. In certain such embodiments, the treatmentsites at the scalp are positioned so as to irradiate as much of thecortex as possible.

Example Wearable Apparatus

FIG. 23A schematically illustrates an example apparatus 500 which iswearable by a patient for treating the patient's brain. The apparatus500 comprises a body 510 and a plurality of indicators 520. The body 510is adapted to be worn over at least a portion of the patient's scalpwhen the apparatus 500 is worn by the patient. The plurality ofindicators 520 correspond to a plurality of treatment site locations atthe patient's scalp where light is to be applied to irradiate at least aportion of the patient's brain. At least one indicator 520 comprises anoptically transmissive portion which is substantially transmissive(e.g., substantially transparent or substantially translucent) to lightemitted from the emission surface 22 to irradiate at least a portion ofthe patient's brain.

In certain embodiments, at least one of the indicators 520 denotes aposition within an area of the patient's scalp corresponding to atreatment site location. In certain such embodiments, the position isthe center of the area of the patient's scalp. The adjacent treatmentsites of certain embodiments have areas which do not overlap one anotheror have perimeters which are spaced from one another. In certain suchembodiments, the perimeters are spaced from one another by at least 10millimeters or at least 25 millimeters.

In certain embodiments, the optically transmissive portion of the atleast one indicator 520 comprises an opening or aperture through thebody 510 at which the beam delivery apparatus 10 can be placed toirradiate the portion of the patient's scalp exposed by the hole oraperture. In other embodiments, the optically transmissive portioncomprises a hollow compartment or cavity that does not extend completelythrough the indicator 520 to the surface of the scalp or skull. Forexample, the indicator 520 can include a mylar film to prevent contactbetween a light source and the patient, thereby avoiding potentialcontamination of a contact portion of the light source by contacting thepatient. The use of the mylar or other suitable protective filmadvantageously enables the light source (or at least the contact portionof the light source) to be reused for multiple patients. In otherembodiments, the light source or a contact portion of the light sourcecan be disposed after a single use.

In certain embodiments, the optically transmissive portion has asubstantially circular perimeter and a diameter in a range between 20millimeters and 50 millimeters or in a range between 25 millimeters and35 millimeters. In certain embodiments, the optically transmissiveportion has a substantially elliptical perimeter with a minor axisgreater than 20 millimeters and a major axis less than 50 millimeters.Other shapes of the optically transmissive portion are also compatiblewith certain embodiments described herein.

In certain embodiments, the plurality of indicators 520 comprises atleast about 10 indicators 520 distributed across the patient's scalp,while in certain other embodiments, the plurality of indicators 520comprises 20 indicators 520. In certain other embodiments, the pluralityof indicators 520 comprises between 15 and 25 indicators 520. In certainembodiments, the optically transmissive portion of each indicator 520has an area of at least 1 cm², in a range between 1 cm² and 20 cm², orin a range between 5 cm² and 10 cm².

In certain embodiments, the body 510 comprises a hood, while in otherembodiments, the body 510 comprises a cap or has another configurationwhich is wearable on the patient's head and serves as a support fororienting the indicators 520 on the patient's head. In certainembodiments, the body 510 comprises a stretchable or pliant materialwhich generally conforms to the patient's scalp. In certain embodiments,the body 510 comprises nylon-backed polychloroprene or Tyvek®. Incertain embodiments, the body 510 is available in different sizes (e.g.,small, medium, large) to accommodate different sizes of heads. Incertain embodiments, the body 510 is disposable after a single use toadvantageously avoid spreading infection or disease between subsequentpatients.

The indicators 520 of certain embodiments are configured to guide anoperator to irradiate the patient's scalp at the corresponding treatmentsite locations sequentially one at a time in a predetermined order.

FIGS. 23B and 23C schematically illustrate the left-side and right-sideof the example apparatus 500, respectively, with labels 522substantially covering the indicators 520 corresponding to the treatmentsites. In certain embodiments, the labels 522 are advantageously used tokeep track of which treatment sites have been irradiated and whichtreatment sites are yet to be irradiated. In certain such embodiments,at least a portion of each label 522 comprises a portion of the body(e.g., a pull-off tab or flap) which is configured to be removed fromthe apparatus 500 when the treatment site corresponding to the indicator520 has been irradiated. In certain embodiments, the labels 522 compriseremovable portions of the body 510 which cover the correspondingindicator 520. In certain such embodiments, prior to irradiating thetreatment site location corresponding to the indicator 520, thecorresponding label 522 can be removed to allow access to the underlyingportion of the patient's scalp.

In certain embodiments, the label 522 has a code sequence which theoperator enters into the controller prior to irradiation so as to informthe controller of which treatment site is next to be irradiated. Incertain other embodiments, each label 522 comprises a bar code or aradio-frequency identification device (RFID) which is readable by asensor electrically coupled to the controller. The controller of suchembodiments keeps track of which treatment sites have been irradiated,and in certain such embodiments, the controller only actuates the lightsource when the beam delivery apparatus 10 is in optical and thermalcommunication with the proper treatment site of the patient's scalp.

FIG. 23D schematically illustrates an example labeling configurationfrom above a flattened view of the apparatus 500 of FIGS. 23B and 23C.The labeling convention of FIG. 23D is compatible with irradiation ofboth halves or hemispheres of the patient's brain. Other labelingconventions are also compatible with embodiments described herein.

In certain embodiments, the labels 522 are advantageously used to guidean operator to irradiate the patient's brain at the various treatmentsites sequentially at each of the treatment sites one at a time throughthe indicators 520 in a predetermined order by optically and thermallycoupling the beam delivery apparatus 10 to sequential treatment sitescorresponding to the indicators 520. For example, for the labelingconfiguration of FIG. 23D, the operator can first irradiate treatmentsite “1,” followed by treatment sites “2,” “3,” “4,” etc. tosequentially irradiate each of the twenty treatment sites one at a time.In certain such embodiments, the predetermined order of the treatmentsites is selected to advantageously reduce temperature increases whichwould result from sequentially irradiating treatment sites in proximityto one another.

In certain embodiments, the predetermined order comprises irradiation ofa first treatment site location on a first side of the patient's scalp(e.g., site “2” of FIG. 23D), then irradiation of a second treatmentsite location on a second side of the patient's scalp (e.g., site “3” ofFIG. 23D), then irradiation of a third treatment site location on thefirst side of the patient's scalp (e.g., site “4” of FIG. 23D). Incertain such embodiments, the predetermined order further comprisesirradiation of a fourth treatment site location on the second side ofthe patient's scalp after irradiation of the third treatment sitelocation. In certain embodiments, two sequentially irradiated treatmentsite locations are separated from one another by at least 25millimeters.

For example, in certain embodiments, the predetermined order comprisesat least a portion of the following sequence of treatment sites:

1. Right anterior frontal

2. Left lateral frontal

3. Right anteroinferior parietal

4. Left posterior mid-parietal

5. Right superior parietal

6. Right lateral frontal

7. Left anterior frontal

8. Left posterior superior parietal

9. Left posteroinferior parietal

10. Right posteroinferior parietal

11. Right posterior superior parietal

12. Right anterior mid-parietal

13. Left anteroinferior parietal

14. Left anterosuperior frontal

15. Left superior occipital

16. Left anterior mid-parietal

17. Right posterior mid-parietal

18. Right anterosuperior frontal

19. Right superior occipital

20. Left superior parietal

For example, the predetermined order of certain embodiments comprisestwo, three, four, or more of these treatment sites in the relative orderlisted above. The sequence of treatment sites of certain embodimentscomprises two, three, four, or more of these treatment sites in arelative order which is the reverse of the sequence listed above. Whilecertain embodiments utilize at least a portion of the relative orderlisted above without irradiation at an additional treatment site betweentwo sequentially listed treatment sites, certain other embodimentsutilize at least a portion of the relative order listed above with oneor more additional treatment sites between two of the sequentiallylisted treatment sites. In certain embodiments, the exact anatomiclocations of each treatment site may be adjusted from those listed aboveto account for variations among the sizes of the heads of the patients(e.g., very large or very small). Thus, in certain embodiments, there issome variability regarding the locations of the treatment sites for anygiven individual.

In certain embodiments, the apparatus 500 serves as a template formarking the patient's scalp to indicate the treatment site locations.The apertures of the apparatus 500 can be used to guide a user to placemarks on the patient's scalp, and the apparatus 500 can then be removedfrom the patient's scalp before the beam delivery apparatus 10 isapplied to the scalp for irradiating the patient's brain. The marksremain on the patient's scalp to guide the operator while the patient'sbrain is irradiated.

FIG. 23E schematically illustrates a top perspective view of anotherexample embodiment of the wearable apparatus 500. The wearable apparatus500 includes a body 510 comprising five panels (a lower left panel 524,an upper left panel 526, a midline panel 528, an upper right panel 530,and a lower right panel 532) and retention assembly 512. The panels ofthe wearable apparatus 500 include one or more position indicators 520that correspond to respective treatment site locations at the patient'sscalp where light is to be applied to irradiate at least a portion ofthe patient's brain. The midline panel 528 advantageously does notinclude any position indicators 520. The position indicators 520 caneach include a label 522 with a number or other indicia to indicate asequence of treatment. At least a portion of the label 522 can beremoved to form an opening or aperture at which the beam deliveryapparatus 10 can be placed to irradiate the portion of the patient'sscalp exposed by the hole or aperture.

The retention assembly 512 can include a retaining member that extendsfrom one side of the apparatus 500 to the other side (e.g., a chinstrap). The retaining member can be formed of a unitary strap element ortwo strap elements that couple together via a coupling mechanism (notshown). The coupling mechanism can comprise any suitable means ofcoupling two strap elements together (e.g., Velcro strips, buckles,snaps, hooks, latches, clips, buttons, ties, or the like). Otherembodiments do not include the retention assembly 512.

FIG. 23F illustrates the lower left panel 524, the upper left panel 526,the upper right panel 530 and the lower right panel 532. The width ofthe lower left panel 524 and the lower right panel 532 (denoted in FIG.23F by “W₁”) can be approximately 10 cm. The length of the lower leftpanel 524 and the lower right panel 532 (denoted in FIG. 23F by “L₁”)can be approximately 20 cm. The length of the upper left panel 526 andthe upper right panel 530 (denoted in FIG. 23F by “L₂”) can be between30 and 35 cm. The width of the upper left panel 526 and the upper rightpanel 530 (denoted in FIG. 23F by “W₂”) can be between about 4 and 6 cm.As shown in FIG. 23F, one or more of the panels (e.g., the upper leftpanel 526) includes a label indicating the front of the body 510 and alabel indicating a size of the body 510. The panels include slits 534that can be sewn together during assembly, thereby providing a contourwhich is configured to at least partially conform to the shape of thepatient's scalp. More or fewer panels can be included in alternativeembodiments.

FIG. 23G illustrates a magnified view of a seam 536 between the upperright panel 530 and the lower right panel 532. The panels of the body510 can comprise Tyvek® material. The Tyvek® panels can be sewn togetherusing a #306 Union Special needle, a #14 Singer needle, or the like. Asshown, a panel can comprise one or more separate portions (e.g.,portions separated by the slits 534) that are sewn together to form acurved shape from a flat panel. The needle used can be a flat tippedneedle or a round-point needle. The stitches can be spaced so as toinclude three to five stitches per inch. Any suitable thread type can beused (for example, glace thread of short staple cotton). In certainembodiments, the maximum overlap between panels or portions of a panelis about two millimeters and the maximum gap between panels or portionsof a panel is about two millimeters. In other embodiments, the panels ofthe body comprise suitable materials other than Tyvek® material, such asfiber-based (natural and/or synthetic) materials and/or polymericmaterials.

FIG. 23H illustrates a rear view of the wearable apparatus 500B. Asshown in FIG. 23H, the wearable apparatus 500B further includes a foldedperimeter portion 538 that extends around the bottom of the wearableapparatus 500B. The peripheral portions of the panels can be insertedwithin the folded perimeter portion 538 and the edges of the foldedperimeter portion 538 can be sewn together to retain the panels. Theretention assembly 512 can also be attached at the perimeter portion538. The width of the perimeter portion 538 can be about fifteenmillimeters. The perimeter portion 538 can comprise elastic-typematerial (e.g., an elastic band). The elastic material can be configuredto aid in securing the body 510 to the head of the patient and can allowfor an adjustable fit for different sized heads.

FIG. 23I schematically illustrates another example embodiment of thewearable apparatus 500. The wearable apparatus 500 includes a body 510and a plurality of position indicators 520. The body 510 can comprise asingle, unitary element that is not separated into individual panels.The body 510 can comprise a stretchable or pliant material whichgenerally conforms to the patient's scalp, such as neoprene,chloroprene, rubber, silicone, thermoplastic resins, other elastomericmaterials, and/or the like. In other embodiments, the body 510 can beformed of a rigid or substantially rigid material in order to preventmovement during irradiation, such as polyethylene, polystyrene,polyvinyl chloride, polytetrafluoroethylene, other plastic or polymericmaterials, and/or the like. In some embodiments, the body 510 comprisesone or more biocompatible materials.

The body 510 can advantageously comprise a material that has relativelyhigh thermal conductivity in order to reduce temperature increases tothe patient's scalp or skin at locations surrounding the positionindicators 520, such as diamond, sapphire, calcium fluoride, and/or thelike. The body 510 can have a thickness between one and ten millimeters;however, other thicknesses can be used as desired and/or required.

The position indicators 520 can be coupled to the body 510 using anysuitable adhesive or coupling method or device, such as epoxy, sutures,welding, molding, adhesive, interference fits, and/or the like. Incertain embodiments, the position indicators 520 can provide indicia oforientation of the wearable apparatus 500 relative to the patient'sscalp. For example, the position indicators 520 that cover the righthemisphere of the brain can be a different color than the positionindicators 520 that cover the left hemisphere of the brain.

The position indicators 520 can comprise any suitable polymer orcombination of polymers, such as thermoplastics, thermosets, andelastomers. The polymers used can be selected based on strength,flexibility, and/or other properties. In certain embodiments, theposition indicators 520 can be formed of two or more distinct materials(not shown). For example, an inner member of the position indicators 520can be formed of one material and an outer member can be formed ofanother material. The outer member can comprise a material having alower durometer value than the inner member, or vice-versa.

FIG. 23J illustrates another example embodiment of the wearableapparatus 500. In certain embodiments, the wearable apparatus 500comprises a plurality of labels 522 with each label 522 in proximity toa corresponding position indicator 520. The labels 522 advantageouslyprovide one or more numbers, letters, or symbols (e.g., bar codes) toeach of the position indicators 520 to distinguish the various positionindicators 520 from one another. Other indicia are possible for thelabels 522, such as varying colors, patterns, and the like. In certainsuch embodiments, the labels 522 are mechanically coupled to thecorresponding indicators so as to be visible to users of the lightsource or light delivery apparatus.

The labels 522 can advantageously be used to keep track of whichtreatment sites have been irradiated and which treatment sites have yetto be irradiated. The labels 522 can also indicate a sequence oftreatment, as described further above in connection with FIGS. 23B-23D.In certain embodiments, the labels 522 can be removable or detachable.For example, a label 522 can be removed from its respective indicator520 immediately before the treatment site corresponding to the indicator520 is irradiated. In other embodiments, the labels 522 are integralwith the wearable apparatus 500 and are not configured to be removedduring treatment, as illustrated by the labels 522 of the wearableapparatus 500 shown in FIG. 23K. The wearable apparatus 500 of FIG. 23Kis described in detail in U.S. Pat. Appl. Pub. No. 2007/0179570, whichis incorporated by reference herein in its entirety.

In other embodiments, a photochromic layer can be positioned to coverone or more of the treatment sites corresponding to the plurality ofposition indicators 520. The photochromic layer can be substantiallyoptically transmissive to light used for the phototherapy treatmentdescribed herein. In certain embodiments, the photochromic layer canchange colors upon being irradiated by light. The photochromic layer canadvantageously be used to indicate to a user which treatment sites havebeen irradiated and which treatment sites have not. In certainembodiments, the photochromic layer comprises one or more photochromicdyes (such as spirooxazines, diarylethenes, axobenzenes, quinones, andthe like) and/or silver or zinc halides. Some photochromic dyes can bemore biocompatible than others. As such, the biocompatibility of thephotochromic dyes can be taken into account in selecting photochromicdyes for use. However, photochromic dyes with low biocompatibilityproperties can be selected for other reasons that may outweighbiocompatibility. In other embodiments, one or more flexible polymershaving low glass transition properties (such as siloxanes or polybutylacrylate) can be attached to the photochromic dyes. In certainembodiments, the flexible polymers are biocompatible.

In certain embodiments, the position indicators 520 are connected toeach other via coupling joints. FIG. 23L illustrates another exampleembodiment of the wearable apparatus 500 in which coupling joints 525mechanically couple the position indicators 520 to one another. Theposition indicators 520 and the coupling joints 525 can be formed as oneintegral piece during the molding process. In other embodiments, theposition indicators 520 can be coupled together using the couplingjoints 525 after the initial molding process. In embodiments where theposition indicators 520 are coupled together after the initial moldingprocess, the coupling joints 525 can comprise complementary matingportions that snap together with the position indicators 520 or witheach other. In embodiments where the position indicators 520 are formedindividually and the wearable apparatus 500 is not formed as an integralunit during the molding process, the position indicators 520 can beconnected by string, tether, elastic, adhesive, and/or the like with orwithout the coupling joints 525. The coupling joints 525 can be formedof the same materials as are the position indicators 520 or of differentmaterials. The use of coupling joints 525 in certain embodimentsincreases the amount of open space of the wearable apparatus 500,thereby reducing the potential for heat retention within the wearableapparatus 500. The absence of the body 510 in certain embodimentsadvantageously minimizes the heat loads transferred to the patients'scalp, brain, or skull.

FIG. 23L illustrates an example embodiment of the wearable headpiecewherein the position indicators 520 and the coupling joints 525 areformed as an integral headpiece unit during the molding process. FIG.23M illustrates an example embodiment of the wearable apparatus 500 inwhich the position indicators 520 are formed of individual units thatare connected together by a tether or connection element 540 (e.g.,string) to form the wearable apparatus 500. The embodiment of FIG. 23Mcan advantageously reduce the cost of manufacture of the wearableapparatus 500.

In certain embodiments, a wearable headpiece can be configured toprovide a force to position a light source (e.g., beam deliveryapparatus 10) relative to the patient's scalp. In certain embodiments,the wearable headpiece is configured to provide an amount of force whichis sufficient to maintain a sufficiently effective interface between thelight source and the patient's scalp for one or more of the following:sufficient uniformity across the irradiated area to permit asubstantially equal distribution of light to a target region of apatient's brain; sufficient optical communication to permit the lightfrom the light source to propagate to the patient's scalp without anundue amount of absorption or reflection; sufficient thermalcommunication to permit a substantial amount of heat transport from thepatient's scalp to the light source; sufficient pressure applied to thepatient's scalp to substantially blanch the irradiated portion of thepatient's scalp. For example, the wearable headpiece can provide one ormore mating interfaces to “lock” the light source at one or more desiredtreatment sites, thereby preventing movement of the light sourcerelative to the patient's brain while irradiating the patient's brainwith the light source.

In certain embodiments, the force of the “lock” provided by theheadpiece is sufficient to hold the light source in place without anyadditional structures or personnel holding the light source. In certainother embodiments, the force of the “lock” provided by the headpiece isonly sufficient to hold the light source in place when used inconjunction with other structures or personnel holding the light source(e.g., supporting the bulk of the weight of the light source). Incertain such embodiments, if the other structure or personnel ceasedholding the light source, the light source would fall away from thepatient's scalp since the force of the “lock” provided by the headpiecealone is insufficient to hold the light source in place. The headpiececan be configured to conform to at least a portion of the patient's head(e.g., scalp and/or forehead). Any of the embodiments illustrated inFIGS. 23A-23M can be adapted to form a wearable headpiece configured toreceive a mating portion of a light source or light delivery apparatus.

FIG. 24 schematically illustrates an example headpiece 550 in accordancewith certain embodiments described herein. In certain embodiments, theheadpiece 550 is configured to conform to at least a portion of thepatient's scalp and comprises a plurality of position indicators 555configured to indicate corresponding treatment site locations at whichlight is to be applied to non-invasively irradiate at least a portion ofthe patient's brain. The plurality of position indicators 555 can bearranged about a patient's head and can be configured to provide a forceto position a light source to irradiate a treatment site location. Atleast one of the position indicators 555 includes an opticallytransmissive region 560 and a mating portion 565 configured toreleasably mate with a complementary mating portion of a light source ora light delivery apparatus.

In certain embodiments, the plurality of position indicators 555comprises at least three position indicators 555 distributed across thepatient's scalp, forehead, and/or neck. In other embodiments, thewearable headpiece 550 comprises between four and thirty positionindicators 555. The position indicators 555 can be spaced such thatadjacent position indicators 555 have perimeters that do not overlap oneanother. In certain embodiments, the perimeters are spaced from oneanother by at least five millimeters, at least ten millimeters or atleast twenty-five millimeters. The position indicators 555 can beintegrally or mechanically coupled. FIG. 24 illustrates an integralconnection 575A and a mechanical connection 575B. In some embodiments,all of the position indicators 555 are integrally coupled. In otherembodiments, all of the position indicators 555 are mechanicallycoupled. The integral connection 575A can be formed, for example, duringa molding process during manufacture. The mechanical connection cancomprise any suitable mechanical connection device or method, such assnap-fit members, adhesive members, glue, epoxy, welding, interferencefits, and/or the like.

In certain embodiments, the optically transmissive region 560 has asubstantially circular perimeter and a diameter in a range betweentwenty millimeters and fifty millimeters or in a range betweentwenty-five millimeters and thirty-five millimeters. In otherembodiments, the optically transmissive region 560 has a substantiallyelliptical perimeter with a minor axis greater than twenty millimetersand a major axis less than fifty millimeters. Other shapes of theoptically transmissive region 560 are also possible. The opticallytransmissive region 560 can be shaped to conform with the shape of amating portion of a light delivery apparatus (such as the beam deliveryapparatus 10 described herein). In certain embodiments, the opticallytransmissive region 560 has an area of at least 1 cm², in a rangebetween 1 cm² and 20 cm², or in a range between 5 cm² and 10 cm².

The mating portion 565 can comprise any mechanism or structure forreleasably mating, or mechanically coupling, with a light deliveryapparatus (e.g., any of the light delivery apparatuses describedherein). The mating portion 565 can be configured to retain the lightdelivery apparatus in a substantially fixed position so as to produce asubstantially equal distribution of light from an emission surface ofthe light source to a target region of irradiation. The mating portion565 can prevent excessive tilting of the light delivery apparatusrelative to the patient's scalp during irradiation. In certainembodiments, by maintaining a substantially even contact or spacingbetween the light delivery apparatus and the patient's skull, the matingportion 565 and can prevent uneven variations in temperature under theemission surface of the light delivery apparatus.

In certain embodiments, the mating portion 565 comprises a rim borderingthe outer perimeter of the aperture or opening. The rim can have aheight between about one millimeter and about fifteen millimeters. Incertain embodiments, the rim can have a height between three and eightmillimeters. The rim can act as a positioning sleeve for an opticalelement of a light delivery apparatus to fit into (e.g., via frictionfit).

The mating portion 565 can be formed of rigid, semi-rigid, or flexiblematerial. In certain embodiments, the mating portion 565 is formed ofmolded plastic. The molded plastic can be composed of any suitablepolymer or combination of polymers, such as thermoplastics, thermosets,and elastomers. The polymers used can be selected based on strength,flexibility, and/or other properties. In other embodiments, the matingportion 565 is formed of rubber or other elastomer materials. In certainembodiments, the mating portion 565 can be formed of two or moredistinct materials. For example, an inner member of the mating portion565 can be formed of one material and an outer member can be formed ofanother material. The outer member can comprise a material having alower durometer value than the inner member or vice versa.

In certain embodiments, the rim of the mating portion 565 is sized andshaped to reversibly mechanically couple a mating portion of a lightdelivery apparatus to the mating portion 565 via friction fit. Forexample, the rim can be sized and shaped to receive, via friction fit,the output optical assembly 20 of the beam delivery apparatus 10 ofFIG. 1. In some embodiments, the inner surface of the rim can betextured to enhance engagement between the mating portions of the rimand the light delivery apparatus. In other embodiments, the innersurface of the rim can be formed of a material, such as a rubber orother elastomer, to increase friction with the mating portion of thelight delivery apparatus.

In certain embodiments, the rim of the mating portion 565 can beslotted, grooved, notched, indented, recessed or the like to releasablymate with a complementary mating portion (e.g., docking element) of thelight delivery apparatus, which may have protrusions, tabs, rivets, orthe like. In some embodiments, the rim includes one or more recesses orslots sized and shaped to mate with one or more protrusions formed onthe complementary mating portion of the light delivery apparatus. Inother embodiments, the rim includes one or more protrusions and thelight delivery apparatus includes one or more complementary recesses orslots. In certain embodiments, the complementary mating portion of thelight delivery apparatus mates with the mating portion 565 of theposition indicator 555 via snap-fit members.

In still other embodiments, the rim of the mating portion 565 can bethreaded so as to receive a complementary threaded portion of the lightdelivery apparatus. Any other suitable means of releasably coupling thelight delivery apparatus to the position indicator 555 can be used inaccordance with various embodiments described herein.

In alternative embodiments, the position indicators 555 can include asubstantially transmissive (e.g., substantially transparent orsubstantially translucent) bag comprising a flexible material (which canbe biocompatible), such as the bags described in connection with FIGS.22A-22C of U.S. Pat. Appl. Pub. No. 2007/0179570, which is incorporatedin its entirety by reference herein. The bags can provide a matinginterface between the light delivery apparatus and the surface of thepatient's scalp, skin, or skull.

In certain embodiments, the bags can be configured to be raised abovethe surface of the scalp, skin or skull while the headpiece 550 is wornby the patient so as to prevent heating of the bag by the body prior totreatment. The bag can configured to move to be in thermal communicationwith the scalp upon the light delivery apparatus being mated to theposition indicator 555. For example, the emission surface of the lightdelivery apparatus can be brought into contact with the bag and the bagcan be depressed by the light delivery apparatus to conform to thesurface of the patient's scalp, skin, or skull. The bag can be used toensure even pressure and to reduce air gaps and back reflections. Thebag can also prevent uneven temperature fluctuations at the treatmentsite. In some embodiments, the bag can include pressure sensors toprovide an indication of adequate blanching of the treatment site. Inother embodiments, pressure sensors can be positioned about theperiphery of the position indicators. Any suitable pressure sensor orpressure sensor can be used, including but not limited to, miniatureflush diaphragm sensors, flat plate sensors, and/or the like.

In other embodiments, the substantially transmissive bag can be providedwith the light delivery apparatus. For example, the substantiallytransmissive bag can be coupled to a contact/emission surface of thelight delivery apparatus and brought into contact with the patient'sscalp or skull when inserted within a position indicator 555.

In certain embodiments, the position indicators 555 can be used toprovide feedback to an operator of the light delivery apparatus. Forexample, the light delivery apparatus can include one or more matingsensors that do not allow the light delivery apparatus to be activateduntil the light delivery apparatus is in sufficient contact with amating portion 565 of a position indicator 555 of the headpiece 550,which may be indicative of a satisfactory mating condition.

In certain embodiments, the mating sensors comprise pressure sensors(not shown). In other embodiments, the mating sensors comprise proximitysensors. In certain embodiments, the light delivery apparatus comprisesfour quadrant-spaced sensors, thereby ensuring even pressure of theemission surface against the surface of the patient's scalp or foreheadbefore activation of the output optical element of the light deliveryapparatus.

The light delivery apparatus can include one or more LEDs configured toprovide an indication to an operator that sufficient contact with themating portion 565 of a position indicator 555 has occurred. The matingindication can also comprise an audible indication (such as a click or abeep).

In certain embodiments, the light delivery apparatus can be mated (e.g.,“locked”) to a first position indicator and can then be activated toirradiate a first treatment site corresponding to the first positionindicator for a first period of time. The light delivery apparatus canthen be removed while the headpiece 550 is still being worn and mated toa second position indicator, with the light delivery apparatus beingactivated to irradiate a second treatment site corresponding to thesecond position indicator for a second period of time upon sufficientcontact. The process can be repeated for each of the positionindicators, as described in more detail herein.

In certain embodiments, the light delivery apparatus is held in themated position by an external support. The external support can be usedto prevent a force from being exerted on the patient's head and/or neckdue to the weight of the light delivery apparatus. The external supportcan be provided whether the body 510 and/or the mating portion 565 isrigid or flexible. In certain embodiments, the external support isprovided by the hand of a person administering the treatment. In otherembodiments, the external support is provided by an external supportstructure that provides a force to maintain the light delivery apparatusin a mated position (e.g., a wall, a tension and/or anchor system,etc.). In still other embodiments, the light delivery apparatus isprovided by a mechanism that introduces little or no load to thepatient's head and/or neck, such as a mechanical arm that extends from astructure that is fixed to a wall, ceiling, or floor. In yet otherembodiments, the light delivery apparatus is substantially lightweightsuch that no external support is required.

In certain embodiments, the mating portion 565 is configured such thatthe light delivery apparatus is automatically released from the matingportion 565 when the external support is removed. For example, if aperson administering the treatment accidentally lets go of the lightdelivery apparatus during the treatment procedure, the mated lightdelivery apparatus can be automatically released or disconnected fromthe mating portion 565 to avoid the exertion of unwanted force on thepatient's head and/or neck or on the wearable headpiece 550 itself.

In certain embodiments, the light delivery apparatus can automaticallyshut off, or terminate, delivery of light when a loss of support (or anexcessive load) is detected. The loss of external support can bedetected by one or more pressure, touch, force, and/or light sensors,detectors, and/or transducers, for example. In other embodiments, themating/locking mechanism is released or disconnected if an angle ofincidence deviates beyond a predetermined threshold angle. The automaticrelease and/or termination of light delivery can be implemented whethersupport is provided externally or by the wearable headpiece 550 itself.Such sensors can comprise a dead-man's switch, a kill switch, or othersafety device or mechanism.

Methods of Light Delivery

FIGS. 25-28 are flow diagrams of example methods for irradiating asurface with light. As described more fully below, the methods aredescribed by referring to the beam delivery apparatus 10 and componentsthereof, as described herein. Other configurations of a beam deliveryapparatus are also compatible with the methods in accordance withembodiments described herein.

The method 610 of FIG. 25 comprises providing a beam delivery apparatus10 in an operational block 612. The beam delivery apparatus 10 comprisesa first portion and a second portion mechanically coupled to the firstportion and in optical communication with the first portion, wherein thefirst portion and the second portion are configured to move relative toone another, as described more fully above. The method 610 furthercomprises placing the second portion in thermal communication with thesurface in an operational block 614 (e.g., releasably operativelycoupling the second portion to the surface). The method 610 furthercomprises irradiating the surface such that the light from the firstportion propagates through the second portion in an operational block616. The method 610 further comprises moving the first portion and thesecond portion relative to one another in response to the second portionbeing placed in thermal communication with the surface in an operationalblock 618.

The method 620 of FIG. 26 comprises providing an optical element 23 inan operational block 622. The optical element 23 comprises asubstantially optically transmissive and substantially thermallyconductive material, and the optical element 23 has a first surface 22and a second surface 24, as described more fully above. The method 620further comprises placing the first surface 22 in thermal communicationwith the irradiated surface in an operational block 624 (e.g.,releasably operatively coupling the first surface 22 to the irradiatedsurface). The method 620 further comprises propagating the light along afirst optical path 32 through the second surface 24 and through thefirst surface 22 to the irradiated surface in an operational block 626.The method 620 further comprises detecting radiation propagating along asecond optical path 82 from at least a portion of the second surface 24,wherein the first optical path 32 and the second optical path 82 have anon-zero angle therebetween in an operational block 628. In certainembodiments, the first surface 22 and the second surface 24 face ingenerally opposite directions, and the first surface 22 is not along thesecond optical path 82.

The method 630 of FIG. 27 comprises providing a thermoelectric assembly90 in an operational block 632. The thermoelectric assembly 90 comprisesa first surface 93 and a second surface 94, and the thermoelectricassembly 90 generally surrounds a first region 97, as described morefully above. The method 630 further comprises providing an outputoptical assembly 20 in an operational block 633. The method 630 furthercomprises releasably mechanically coupling the first surface 93 of thethermoelectric assembly 90 to the output optical assembly 20 so that thefirst surface 93 is in thermal communication with the output opticalassembly 20 in an operational block 634. The method 630 furthercomprises cooling the first surface 93 and heating the second surface 94in an operational block 636. The method 630 further comprisespropagating light through the first region 97 to impinge the irradiatedsurface in an operational block 638. In certain embodiments, the firstsurface 22 and the second surface 24 face in generally oppositedirections, and the first surface 22 is not along the second opticalpath 82.

In certain embodiments, the output optical assembly 20 comprises anoptical element 23 and a thermally conductive portion 25 generallysurrounding a second region 28. The thermally conductive portion 25 isin thermal communication with the optical element 23. In certain suchembodiments, releasably mechanically coupling the first surface 93 tothe output optical assembly 20 comprises releasably mechanicallycoupling the first surface 93 to the thermally conductive portion 25. Incertain such embodiments, the method 630 further comprises placing theoptical element 23 in thermal communication with the irradiated surfaceand propagating the light comprises transmitting the light through thefirst region 97, the second region 28, and the optical element 23 toimpinge the irradiated surface. In certain embodiments, the method 630further comprises providing a heat sink 100 in thermal communicationwith the second surface 94 of the thermoelectric assembly 90. The heatsink 100 generally surrounds a third region 107, and propagating thelight comprises transmitting the light through the third region 107, thefirst region 97, the second region 28, and the optical element 23.

The method 640 of FIG. 28 comprises emitting a light beam from anemission surface 22 of an optical element 23 in an operational block642. The light beam at the emission surface 22 has one or morewavelengths in a range of about 630 nanometers to about 1064 nanometers,a cross-sectional area greater than about 2 cm², and a time-averagedirradiance in a range of about 10 mW/cm² to about 10 W/cm² across thecross-sectional area, as described more fully above. The method 640further comprises removing heat from the emission surface 22 at a ratein a range of about 0.1 Watt to about 5 Watts in an operational block644. The method 640 further comprises impinging the irradiated surfacewith the light beam in an operational block 646.

The method 640 of certain embodiments further comprises placing theemission surface 22 in thermal communication with the irradiated surface(e.g., using the emission surface 22 to apply pressure to the irradiatedsurface by applying a force to the emission surface 22 in a directiongenerally towards the irradiated surface, the pressure greater thanabout 0.1 pound per square inch or about equal to 2 pounds per squareinch).

In certain embodiments, impinging the irradiated surface with the lightbeam is performed for a time period of 10 seconds to two hours, for atime period of 60 seconds to 600 seconds, or for a time period of about120 seconds. In certain embodiments, the steps of the operational blocks642, 644, and 646 are performed concurrently. The method 640 of certainembodiments further comprises moving the emission surface 22 from afirst position at which a first portion of the irradiated surface isimpinged by the light beam to a second position, and repeating the stepsof the operational blocks 642, 644, and 646 so as to impinge a secondportion of the irradiated surface by light emitted from the emissionsurface 22. The first portion and the second portion do not overlap oneanother in certain embodiments. This method can be repeated so as toimpinge twenty portions of the irradiated surface by light emitted fromthe emission surface 22. In certain such embodiments, the twentyportions of the irradiated surface do not overlap one another. However,the portions of the patient's brain irradiated by impinging these twentyportions of the patient's scalp do overlap one another in certainembodiments.

The irradiated surface of certain embodiments of the methods describedabove in reference to FIGS. 25-28 comprises a portion of the patient'sscalp or skull. In certain other embodiments, the surface irradiated bythe light comprises a portion of a light-detection system configured tomeasure one or more parameters of light irradiating the surface (e.g.,irradiance, total power, beam size, beam profile, beam uniformity). Incertain such embodiments, the method further comprises measuring the oneor more parameters of the light from the apparatus 10 impinging thesurface. For example, the light-detection system can comprise a portionof the apparatus 10 configured to test the light beam emitted from theemission surface 22 immediately prior to treatment of the patient. Inthis way, the light-detection system can be used to ensure that thelight beam applied to the patient's scalp or skull has the desiredtreatment parameters.

In certain embodiments, a patient is treated by identifying a pluralityof treatment sites (e.g., at least about 10) on the patient's scalp orskull, directing a light beam to each of the treatment sites, andirradiating each treatment site with the light beam. As described morefully below, in certain embodiments, the treatment sites are identifiedusing an apparatus comprising a plurality of indicators, each of whichcorresponds to a treatment site location. In certain such embodiments,the treatment sites are sequentially irradiated by a light beam from theemission surface. In certain other embodiments, the treatment sites areinstead identified by other indicia. For example, each of the treatmentsites can be identified by markings made on the scalp, or by structuresplaced in proximity to the scalp or skull. Each of the treatment sitescan then be irradiated. In certain embodiments, each of the treatmentsites is irradiated by a light beam from the emission surface while theemission surface is in contact with the scalp or skull or in contactwith an intervening optically transmissive element which contacts thescalp or skull. In certain other embodiments, the scalp or skull is notcontacted by either the emission surface or an intervening element. Incertain embodiments, each of the treatment sites is irradiated using asingle beam delivery apparatus which is sequentially moved from onetreatment site to another. In certain other embodiments, a plurality ofbeam delivery apparatuses are used to irradiate multiple treatment sitesconcurrently. In certain such embodiments, the number of beam deliveryapparatuses is fewer than the number of treatments sites, and theplurality of beam delivery apparatuses are sequentially moved tosequentially irradiate the treatment sites.

FIG. 29A is a flow diagram of an example method 700 for controllablyexposing at least one predetermined area of a patient's scalp or skullto laser light to irradiate the patient's brain. As described more fullybelow, the method 700 is described by referring to the wearableapparatus 500 and the beam delivery apparatus 10 described herein. Otherconfigurations of a wearable apparatus 500 and a beam delivery apparatus10 are also compatible with the method 700 in accordance withembodiments described herein.

The method 700 comprises providing a beam delivery apparatus 10 in anoperational block 710. In certain embodiments, the beam deliveryapparatus 10 comprises an emission surface 22 configured to emit a lightbeam. Other configurations of the beam delivery apparatus 10 besidesthose described above are also compatible with certain embodimentsdescribed herein.

The method 700 further comprises placing a wearable apparatus 500 overthe patient's scalp in an operational block 720. The apparatus 500comprises a body 510 and a plurality of indicators 520. In certainembodiments, each indicator 520 is substantially transmissive to thelight beam emitted from the emission surface 22. Other configurations ofthe wearable apparatus 500 besides those described above are alsocompatible with certain embodiments described herein.

The method 700 further comprises placing the emission surface 22 inthermal communication with a treatment site of the patient's scalp orskull to be irradiated in an operational block 730. The method 700further comprises irradiating the treatment site with light emitted bythe emission surface 22 in an operational block 740. In certainembodiments, the light beam is transmitted through the indicator 520.

In certain embodiments, providing the light emitting apparatus 600 inthe operational block 710 comprises preparing the beam deliveryapparatus 10 for use to treat the patient. In certain embodiments,preparing the beam delivery apparatus 10 comprises cleaning the portionof the beam delivery apparatus 10 through which laser light isoutputted. In certain embodiments, preparing the beam delivery apparatus10 comprises verifying a power calibration of laser light outputted fromthe beam delivery apparatus 10. Such verification can comprise measuringthe light intensity output from the beam delivery apparatus 10 andcomparing the measured intensity to an expected intensity level.

In certain embodiments, placing the wearable apparatus 500 over thepatient's scalp in the operational block 720 comprises preparing thepatient's scalp for treatment. For example, in certain embodiments,preparing the patient's scalp for treatment comprises removing hair fromthe predetermined areas of the patient's scalp to be irradiated.Removing the hair (e.g., by shaving) advantageously reduces heating ofthe patient's scalp by hair which absorbs laser light from the beamdelivery apparatus 10. In certain embodiments, placing the wearableapparatus 500 over the patient's scalp in the operational block 720comprises positioning the wearable apparatus 500 so that each indicator520 is in position to indicate a corresponding portion of the patient'sscalp or skull to be irradiated.

In certain embodiments, placing the emission surface 22 in thermalcommunication with the treatment site in the operational block 730comprises pressing the emission surface 22 to the treatment site. Incertain embodiments, by pressing the emission surface 22 against thetreatment site in this way, pressure is applied to the portion of thepatient's scalp of the treatment site so as to advantageously blanch theportion of the patient's scalp to be irradiated.

In certain embodiments, irradiating the treatment site of the patient'sscalp or skull in the operational block 740 comprises triggering theemission of light from the emission surface 22 by pressing the emissionsurface 22 against the treatment site with a predetermined level ofpressure. In certain embodiments, the emission of light from theemission surface 22 continues only if a predetermined level of pressureis maintained by pressing the emission surface 22 against the treatmentsite. In certain embodiments, light is emitted from the emission surface22 to the treatment site for a predetermined period of time.

In certain embodiments, the method further comprises irradiatingadditional treatment sites of the patient's scalp or skull during atreatment process. For example, after irradiating a first treatment sitecorresponding to a first indicator, as described above, the emissionsurface 22 can be placed in contact with a second indicatorcorresponding to a second treatment site and irradiating the secondtreatment site with light emitted by the emission surface 22. Thevarious treatment sites of the patient's scalp or skull can beirradiated sequentially to one another in a predetermined sequence. Incertain embodiments, the predetermined sequence is represented by theindicators of the wearable apparatus 500. In certain such embodiments,the beam delivery apparatus 10 comprises an interlock system whichinterfaces with the indicators of the wearable apparatus 500 to preventthe various treatment sites from being irradiated out of thepredetermined sequence.

FIG. 29B is a flow diagram of an example method 750 for providingphototherapy to at least a portion of a patient's brain. As describedmore fully below, the method 750 is described by referring to thewearable headpiece 550 and a light source (e.g., the beam deliveryapparatus 10) described herein. Other configurations of a wearableheadpiece 550 and a light source are also compatible with the method 750in accordance with embodiments described herein.

The method 750 comprises providing a light source (e.g., beam deliveryapparatus 10) in an operational block 755. In certain embodiments, thelight source comprises an emission surface configured to emit a lightbeam.

The method 750 further comprises placing a wearable headpiece 550 overthe patient's scalp in an operational block 760. The headpiece 550comprises a plurality of position indicators 555. In certainembodiments, at least one of the position indicators 555 includes anoptically transmissive region that is substantially transmissive to thelight emitted from the emission surface of the light source and a matingportion that is configured to releasably mate with a complementaryportion of the light source. Other configurations of the wearableheadpiece 550 besides those described above are also compatible withcertain embodiments described herein.

The method 750 further comprises reversibly mechanically coupling thelight source to a first portion of the headpiece 550 while the headpiece550 is on the patient's head in an operational block 765. The mechanicalcoupling can occur via friction fit, threading, snap-fit members, or anyother suitable coupling means. The method 750 further comprisesirradiating a first treatment site with light emitted by the emissionsurface of the light source while the light source is mechanicallycoupled to the first portion of the headpiece 550 in an operation block770. The first portion of the headpiece 550 applies a first force to thelight source such that light emitted by the light source non-invasivelyirradiates at least a first portion of the patient's brain bypropagating through the first treatment site of the patient's scalp.

The method 750 further comprises decoupling the light source from thefirst portion of the headpiece 550 while the headpiece 550 remains onthe patient's head in an operational block 775. In certain embodiments,the method 750 further comprises irradiating additional treatment sitesof the patient's scalp or skull during a treatment process. For example,operational blocks 765 through 775 can be repeated at a second portionof the headpiece 550 by reversibly mechanically coupling the lightsource to a second portion of the headpiece 550 while the headpiece 550is on the patient's head, wherein the headpiece 550 applies a secondforce to the light source such that light emitted by the light sourcewhile the light source is mechanically coupled to the second portion ofthe headpiece 550 non-invasively irradiates at least a second portion ofthe patient's brain by propagating through a second treatment site ofthe patient's scalp and then decoupling the light source from the secondportion of the headpiece 550 while the headpiece 550 remains on thepatient's head.

In certain embodiments, the first portion of the patient's brain and thesecond portion of the patient's brain at least partially overlap oneanother and the first treatment site and the second treatment site donot at least partially overlap one another. In certain embodiments, thefirst portion of the headpiece 550 is a first position indicator 555 andthe second portion of the headpiece 550 is a second position indicator555.

In certain embodiments, the method 750 comprises verifying (e.g.,through the use of pressure sensors) that a sufficient pressure existsbetween a mating portion of the light source and the first portion ofthe headpiece 550 before irradiating the first treatment site atoperational block 770. In other embodiments, multiple light sources canbe reversibly mechanically coupled to portions of the headpiece 550simultaneously.

FIG. 30 is a flow diagram of another example method 800 for treating apatient's brain. The method 800 is described below by referring to thewearable apparatus 500 and the beam delivery apparatus 10 describedherein. Other configurations of a wearable apparatus 500 and a beamdelivery apparatus 10 are also compatible with the method 700 inaccordance with embodiments described herein.

The method 800 comprises noninvasively irradiating a first area of atleast 1 cm² of the patient's scalp or skull with laser light during afirst time period in an operational block 810. The method 800 furthercomprises noninvasively irradiating a second area of at least 1 cm² ofthe patient's scalp or skull with laser light during a second timeperiod in an operational block 820. The first area and the second areado not overlap one another, and the first time period and the secondtime period do not overlap one another. In certain embodiments, thefirst area and the second area are spaced from one another by at least10 millimeters. In certain embodiments, the first area is over a firsthemisphere of the brain, and the second area is over a second hemisphereof the brain.

In certain embodiments, the method 800 further comprises identifying thefirst area and the second area by placing a template over the patient'sscalp. The template comprises a first indicator of the first area and asecond indicator of the second area. For example, the first indicatorcan comprise a first opening in the template and the second indicatorcan comprise a second opening in the template. In certain embodiments,the method 800 further comprises placing a laser light source at a firstposition to noninvasively irradiate the first area and moving the laserlight source to a second position to noninvasively irradiate the secondarea.

In certain embodiments, the method 800 further comprises increasing thetransmissivity of the first area to the laser light and increasing thetransmissivity of the second area to the laser light. Increasing thetransmissivity of the first area can comprise applying pressure to thefirst area to at least partially blanch the first area, removing hairfrom the first area prior to noninvasively irradiating the first area,applying an index-matching material to the first area, or a combinationof two or more of these measures. Increasing the transmissivity of thesecond area can comprise applying pressure to the second area to atleast partially blanch the second area, removing hair from the secondarea prior to noninvasively irradiating the second area, applying anindex-matching material to the second area, or a combination of two ormore of these measures.

FIG. 38 is a flow diagram of an example method 900 for treating apatient's brain in accordance with certain embodiments described herein.The method 900 comprises providing a patient in an operational block 910whose brain has experienced at least one neurologic disorder (e.g.,Alzheimer's Disease, Parkinson's Disease, Huntington's disease,depression) or physical trauma (e.g., an ischemic stroke or a traumaticbrain injury) resulting in a blood flow reduction to at least some braincells of the patient. The method 900 further comprises irradiating atleast a portion of the patient's scalp or skull with a pulsed light beamcomprising a plurality of pulses transmitted through the patient's skullin an operational block 920. The pulsed light beam has a temporalprofile which supports one or more intercellular or intracellularbiological processes involved in the survival or regeneration of braincells. For example, the pulsed light beam of certain embodimentscomprises an average irradiance per pulse and a temporal profilecomprising a temporal pulse width and a duty cycle sufficient topenetrate the skull to modulate membrane potentials, thereby enhancingcell survival (e.g., to cause increased neuron survival), cell function,or both of the irradiated brain cells.

In certain embodiments, providing the patient comprises identifying apatient whose brain has experienced at least one neurologic disorder orphysical trauma. In certain such embodiments, identifying the patientcomprises communicating with the patient, or with another person withknowledge regarding the patient's health or experiences, and determiningwhether the patient has experienced a neurologic disorder or a physicaltrauma to the brain. In certain other embodiments, identifying thepatient comprises examining the patient's body (e.g., head or skull) forevidence of the patient having experienced a physical trauma to thebrain. This examination in certain embodiments includes use of invasiveor non-invasive medical devices, techniques, or probes (e.g., a magneticresonance imaging device). In certain other embodiments, identifying thepatient comprises administering a test of the patient's mental faculties(e.g., to determine the patient's abilities on a neurologic functionscale) for evidence indicating that the patient has experienced aneurologic disorder or a physical trauma to the brain. Persons skilledin the art are able to identify the patient in accordance with variousembodiments described herein. In certain embodiments, providing thepatient comprises receiving information regarding the results of aprevious identification (e.g., communication, examination, or testadministration) of the patient as one who has experienced at least oneneurologic disorder or physical trauma.

In certain embodiments, irradiating at least a portion of the patient'sscalp or skull with a pulsed light beam comprises generating the pulsedlight beam and directing the pulsed light beam to irradiate at least aportion of the patient's scalp or skull. The pulsed light beam ofcertain embodiments has a wavelength, time-averaged irradiance, beamsize, beam profile, divergence, temporal pulse width, duty cycle,repetition rate, and peak irradiance per pulse, as described herein.Various light delivery apparatuses can be used to generate the pulsedlight beam and to direct the pulsed light beam towards the patient'sscalp or skull, including but not limited to, the apparatus disclosedherein or by U.S. Pat. Nos. 6,214,035; 6,267,780; 6,273,905; 6,290,714;7,303,578; and 7,575,589 and in U.S. Pat. Appl. Publ. Nos. 2005/0107851A1 and 2009/0254154 A1, each of which is incorporated in its entirety byreference herein.

In certain embodiments, irradiating at least a portion of the patient'sscalp or skull comprises identifying one or more treatment sites (e.g.,at least 10, between 2 and 100, or between 15 and 25) and sequentiallyirradiating the treatment sites with the pulsed light beam. In certainembodiments, the one or more treatment sites are identified as describedherein (e.g., by an apparatus worn by the patient and comprising one ormore apertures, by markings made on the scalp, or by structures placedin proximity to the scalp or skull). In certain embodiments, eachtreatment site is irradiated by an apparatus in contact with the scalpor skull or not in contact with the scalp or skull as described herein.In certain such embodiments, the irradiated portion of the scalp isblanched during the irradiation, is not blanched during the irradiation,is cooled during the irradiation, or is not cooled during theirradiation.

In certain embodiments, the patient's scalp is prepared for treatmentprior to irradiation. For example, in certain embodiments, preparing thepatient's scalp for treatment comprises removing at least a portion ofthe hair or substantially all the hair from the predetermined areas ofthe patient's scalp to be irradiated. Removing the hair (e.g., byshaving so that the irradiated portion of the scalp is substantiallyfree of hair) advantageously reduces heating of the patient's scalp byhair which absorbs the light from the light emitting apparatus. Incertain other embodiments, the hair is not shaved or otherwise removedprior to irradiation. For example, irradiating the patient's scalp canbe performed using pulsed light with wavelengths, temporal pulse widths,and duty cycles which avoid adverse heating of the patient's scalp dueto absorption of light by the hair.

In certain embodiments, the parameters of the pulsed light beam used toirradiate the patient's scalp or skull are selected to perform one ormore of the following: (i) to cause increased neuron survival of thebrain cells following at least one physical trauma, (ii) to support oneor more intercellular or intracellular biological processes involved inthe survival or regeneration of brain cells, or (iii) to modulatemembrane potentials in order to enhance, restore, or promote cellsurvival, cell function, or both of the irradiated brain cells followinga traumatic brain injury. In one example such embodiment, the pulsedlight beam at the emission surface of the apparatus has a beam diameterin a range between 10 millimeters and 40 millimeters, an averageirradiance per pulse in a range between 10 mW/cm² and 10 W/cm², one ormore wavelengths in a range between 780 nanometers and 840 nanometers,and a temporal pulsewidth in a range between 0.1 millisecond and 150seconds or between 0.1 millisecond and 300 milliseconds. The duty cycleof certain embodiments can be in a range between 10% and 30%. Otherranges of these parameters of the pulsed light beam can be selected inaccordance with various other embodiments described herein.

Neurologic Function Scales

Neurologic function scales can be used to quantify or otherwisecharacterize the efficacy of various embodiments described herein.Neurologic function scales generally use a number of levels or points,each point corresponding to an aspect of the patient's condition. Thenumber of points for a patient can be used to quantify the patient'scondition, and improvements in the patient's condition can be expressedby changes of the number of points. One example neurologic functionscale is the National Institute of Health Stroke Scale (NIHSS) which canbe used for short-term measurements of efficacy (e.g., at 24 hours). TheNIHSS is a comprehensive and objective scale which utilizes aseven-minute physical exam, a 13 item scale, and 42 points. Zero pointscorresponds to a normal exam, 42 points (the maximum) corresponds tobasically comatose, and over 15-20 points indicates that the effects ofthe stroke are particularly severe. The NIHSS has previously been usedfor tPA trials in the treatment of ischemic stroke, with a 4-pointchange over 24 hours and an overall score of 0 or 1 at three monthsindicative of a favorable outcome. Other neurologic function scalesinclude, but are not limited to, modified Rankin Scale (mRS), BarthelIndex (BI), Glasgow Outcome, Glasgow Coma Scale, Canadian NeurologicScale, and stroke impact scales such as SIS-3 and SIS-16. In somescales, an improvement in the patient's condition is indicated by areduction in the number of points. For example, the mRS has six pointstotal, with zero corresponding to normal functioning, and sixcorresponding to death. In other scales, an improvement in the patient'scondition is indicated by an increase in the number of points. Forexample, in the Glasgow Outcome which has five points, zero correspondsto death and five corresponds to full recovery. In certain embodiments,two or more of the neurologic function scales can be used in combinationwith one another, and can provide longer-term measurements of efficacy(e.g., at three months).

For stroke, the U.S. Food and Drug Administration (FDA) and theneurologic community have expressed interest in clinical patientoutcomes at 90 days post stroke. Two of the most common and acceptedinstruments for measuring efficacy are the NIHSS and mRS. The FDA isflexible in the way that neurologic function scales can be used. Forexample, it is acceptable to use the mRS (i) in dichotomized fashionwith success at score of 0-1 or (ii) it can be analyzed looking atshifts in the scale showing improvement of patients along the five-pointscale.

In certain embodiments described herein, a patient exhibiting symptomsof an ischemic stroke is treated by irradiating a plurality of treatmentsites on the patient's scalp. The irradiation is performed utilizingirradiation parameters (e.g., wavelength, irradiance, time period ofirradiation, etc.) which, when applied to members of a treated group ofpatients, produce at least a 2% average difference between the treatedgroup and a placebo group on at least one neurologic function scaleanalyzed in dichotomized or any other fashion and selected from thegroup consisting of: NIHSS, mRS, BI, Glasgow Outcome, Glasgow ComaScale, Canadian Neurologic Scale, SIS-3, and SIS-16. Certain otherembodiments produce at least a 4% average difference, at least a 6%average difference, or at least a 10% average difference between treatedand placebo groups on at least one of the neurologic function scalesanalyzed in dichotomized or any other fashion and selected from thegroup consisting of: NIHSS, mRS, BI, Glasgow Outcome, Glasgow ComaScale, Canadian Neurologic Scale, SIS-3, and SIS-16. In certainembodiments, the irradiation of the patient's scalp produces a change inthe patient's condition. In certain such embodiments, the change in thepatient's condition corresponds to a change in the number of pointsindicative of the patient's condition. In certain such embodiments, theirradiation produces a change of one point, a change of two points, achange of three points, or a change of more than three points on aneurologic function scale.

Various studies have been conducted to provide information regarding theinteraction of laser light with the human body and the effectiveness andsafety of transcranial light therapy (TLT). For example, (i) powerdensity measurements have been made to determine the transmission oflaser light having a wavelength of approximately 808 nanometers throughsuccessive layers of human brain tissue; (ii) in vivo thermalmeasurements have been made to determine the heating effect in livingtissue of laser light having a wavelength of approximately 808nanometers; (iii) NEST-1 and NEST-2 phototherapy trials (“Infrared lasertherapy for ischemic stroke: a new treatment strategy: Results of theNeuroThera Effectiveness and Safety Trial-1 (NEST-1),” Stroke, 2007;38:1843-1849, incorporated in its entirety by reference herein, and“Effectiveness and safety of transcranial laser therapy for acuteischemic stroke,” Stroke, 2009:40:1359-1364, which is incorporated inits entirety by reference herein), suggest the safety and efficacy oftranscranial light therapy (TLT) for treatment of humans with ischemicstroke; (iv) examination of continuous wave (CW) and pulse wave (PW)NILT delivery frequency settings to determine optimally efficacioustreatment regimens using the RSCEM (see, P. A. Lapchak, L. De Taboada,“Transcranial near infrared laser treatment (NILT) increases corticaladenosine-5′-triphosphate (ATP) content following embolic strokes inrabbits,” Brain Research, Vol. 1306, pp. 100-105 (2010), which isincorporated in its entirety by reference herein; (v) study of low-levellaser therapy (LLLT) for TBI using the mouse closed-head injury (CHI)model by studying the neurobehavioral and histological outcome of thetraumatized mice (see, A. Oron et al., “Low-Level Laser Therapy AppliedTranscranially to Mice following Traumatic Brain Injury SignificantlyReduces Long-Term Neurological Deficits,” Journal of Neurotrauma, Volume24, Number 4, 2007 which is incorporated in its entirety by referenceherein); and (vi) study of infrared Transcranial Laser Therapy (TLT) forefficacy in an amyloid precursor peptide (APP) transgenic mouse model ofAlzheimer's Disease (AD). These various studies are described more fullyin U.S. Pat. Appl. Publ. No. US 2009/0254154 A1, which is incorporatedin its entirety by reference herein.

The explanations and illustrations presented herein are intended toacquaint others skilled in the art with the invention, its principles,and its practical application. Those skilled in the art may adapt andapply the invention in its numerous forms, as may be best suited to therequirements of a particular use. Accordingly, the specific embodimentsof the present invention as set forth are not intended as beingexhaustive or limiting of the invention.

What is claimed is:
 1. A method of treating a brain of a patient, themethod comprising: noninvasively irradiating a first area of at least 1cm² of a head of the patient with light having an irradiance between 100μW/cm² to 10 W/cm² and a wavelength between 630 nanometers to 1064nanometers during a first time period to irradiate a first area of atarget subsurface tissue of the brain of the patient below a dura of thepatient; noninvasively irradiating a second area of at least 1 cm² ofthe head of the patient with light having an irradiance between 100μW/cm² to 10 W/cm² and a wavelength between 630 nanometers to 1064nanometers during a second time period to irradiate a second area of thetarget subsurface tissue of the brain of the patient below the dura ofthe patient, the second area of the target subsurface tissue of thebrain of the patient partially overlapping the first area of the targetsubsurface tissue of the brain of the patient; and identifying the firstarea of the head of the patient and the second area of the head of thepatient by placing a template over the head of the patient, wherein thetemplate comprises a first indicator of the first area of the head ofthe patient and a second indicator of the second area of the head of thepatient, wherein the first area of the head of the patient and thesecond area of the head of the patient do not overlap one another, andwherein the first time period and the second time period do not overlapone another.
 2. The method of claim 1, wherein the first indicatorcomprises a first opening in the template and the second indicatorcomprises a second opening in the template.
 3. The method of claim 1,further comprising placing a light source at a first position tononinvasively irradiate the first area of the head of the patient andmoving the light source to a second position to noninvasively irradiatethe second area of the head of the patient.
 4. The method of claim 1,further comprising increasing a transmissivity of the first area of thehead of the patient and increasing a transmissivity of the second areaof the head of the patient.
 5. The method of claim 4, wherein increasingthe transmissivity of the first area of the head of the patientcomprises applying pressure to the first area of the head of the patientto at least partially blanch the first area of the head of the patient.6. The method of claim 4, wherein increasing the transmissivity of thefirst area of the head of the patient comprises removing hair from thefirst area of the head of the patient prior to noninvasively irradiatingthe first area of the head of the patient.
 7. The method of claim 4,wherein increasing the transmissivity of the first area of the head ofthe patient comprises applying an index-matching material to the firstarea of the head of the patient.
 8. The method of claim 1, wherein thefirst area of the head of the patient and the second area of the head ofthe patient are spaced from one another by at least 10 millimeters. 9.The method of claim 1, wherein the patient has suffered an ischemicstroke or a traumatic brain injury.
 10. The method of claim 1, whereinthe light has a duty cycle between 1% to 80%.
 11. The method of claim10, wherein the light has a peak irradiance between 12.5 mW/cm² to 1000W/cm².
 12. The method of claim 10, wherein the light has a time-averagedirradiance between 10 mW/cm² to 10 W/cm².
 13. The method of claim 10,wherein the light has a temporal pulsewidth between 0.001 millisecond to150 seconds.
 14. The method of claim 10, wherein the light has atime-averaged irradiance between 0.01 mW/cm² to 1 W/cm².
 15. The methodof claim 1, wherein no portion of the head of the patient is heated to atemperature greater than 60 degrees Celsius.
 16. The method of claim 1,wherein no portion of the brain of the patient is heated to atemperature greater than 5 degrees Celsius above its baselinetemperature.
 17. The method of claim 1, wherein the light is laserlight.
 18. A method of treating a brain of a patient, the methodcomprising: noninvasively irradiating a first area of at least 1 cm² ofa head of the patient with light having an irradiance between 100 μW/cm²to 10 W/cm² and a wavelength between 630 nanometers to 1064 nanometersduring a first time period to irradiate a first area of a targetsubsurface tissue of the brain of the patient below a dura of thepatient; and noninvasively irradiating a second area of at least 1 cm²of the head of the patient with light having an irradiance between 100μW/cm² to 10 W/cm² and a wavelength between 630 nanometers to 1064nanometers during a second time period to irradiate a second area of thetarget subsurface tissue of the brain of the patient below the dura ofthe patient, the second area of the target subsurface tissue of thebrain of the patient partially overlapping the first area of the targetsubsurface tissue of the brain of the patient, wherein the first area ofthe head of the patient and the second area of the head of the patientdo not overlap one another, wherein the first time period and the secondtime period do not overlap one another, and wherein the first area ofthe head of the patient is over a first hemisphere of the brain of thepatient, and the second area of the head of the patient is over a secondhemisphere of the brain of the patient.
 19. The method of claim 18,further comprising identifying the first area of the head of the patientand the second area of the head of the patient by placing a templateover the head of the patient, wherein the template comprises a firstindicator of the first area of the head of the patient and a secondindicator of the second area of the head of the patient, wherein thefirst indicator comprises a first opening in the template and the secondindicator comprises a second opening in the template.
 20. The method ofclaim 18, further comprising placing a light source at a first positionto noninvasively irradiate the first area of the head of the patient andmoving the light source to a second position to noninvasively irradiatethe second area of the head of the patient.
 21. The method of claim 18,further comprising increasing a transmissivity of the first area of thehead of the patient and increasing a transmissivity of the second areaof the head of the patient.
 22. The method of claim 21, whereinincreasing the transmissivity of the first area of the head of thepatient comprises applying pressure to the first area of the head of thepatient to at least partially blanch the first area of the head of thepatient.
 23. The method of claim 21, wherein increasing thetransmissivity of the first area of the head of the patient comprisesremoving hair from the first area of the head of the patient prior tononinvasively irradiating the first area of the head of the patient. 24.The method of claim 21, wherein increasing the transmissivity of thefirst area of the head of the patient comprises applying anindex-matching material to the first area of the head of the patient.25. The method of claim 18, wherein the first area of the head of thepatient and the second area of the head of the patient are spaced fromone another by at least 10 millimeters.
 26. The method of claim 18,wherein the patient has suffered an ischemic stroke or a traumatic braininjury.
 27. The method of claim 18, wherein the light has a duty cyclebetween 1% to 80%.
 28. The method of claim 27, wherein the light has apeak irradiance between 12.5 mW/cm² to 1000 W/cm².
 29. The method ofclaim 27, wherein the light has a time-averaged irradiance between 10mW/cm² to 10 W/cm².
 30. The method of claim 27, wherein the light has atemporal pulsewidth between 0.001 millisecond to 150 seconds.
 31. Themethod of claim 27, wherein the light has a time-averaged irradiancebetween 0.01 mW/cm² to 1 W/cm².
 32. The method of claim 27, wherein thelight is laser light.
 33. The method of claim 18, wherein no portion ofthe head of the patient is heated to a temperature greater than 60degrees Celsius.
 34. The method of claim 18, wherein no portion of thebrain of the patient is heated to a temperature greater than 5 degreesCelsius above its baseline temperature.